Macrocyclic Spiro Pyrimidine Derivatives

ABSTRACT

Macrocyclic spiro pyrimidine compounds, compositions comprising such compounds, methods for making the compounds, and methods of treating and preventing the progression of diseases, conditions, and disorders using such compounds and compositions are described herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to provisional application Ser. No.61/035,440 filed Mar. 11, 2008, which is incorporated herein byreference.

BACKGROUND OF THE INVENTION

1. Technical Field

The invention relates to macrocyclic spiro pyrimidine compounds,compositions comprising the compounds, methods for making the compounds,and methods of treating conditions and disorders using such compoundsand compositions.

2. Description of Related Technology

Histamine modulates a number of physiological activities, acting throughspecific histamine receptors (reviewed in Parsons and Ganellin, BritishJournal of Pharmacology (2006) 147, S127-S135; Igaz and Hegyesi, inHistamine: Biology and Medical Aspects (2004), 89-96; Editor(s): A.Falus; Published S. Karger A G, Basel). Four histamine receptors havebeen identified as playing distinct physiological roles. These are thehistamine H₁ receptor, the histamine H₂ receptor, the histamine H₃receptor, and the histamine H₄ receptor. Compounds that modulate, oraffect, the activity of these receptors may be used to treat diseases.For example, the well-known role of H₁ receptors in modulating allergicreaction has led to the clinical development of drugs that treatallergic rhinitis and other diseases by antagonizing the action ofnaturally-occurring, or endogenous, histamine in the body. Histamine H₂receptor antagonists have been developed and proven clinically useful intreating diseases associated with excess stomach acidity. The histamineH₃ receptor is found predominantly on nerve terminals in the centralnervous system (CNS) and the peripheral nervous system, i.e., periphery,and antagonists of this receptor have been documented in studies thatbenefit mammalian cognitive process, improve wakefulness, suppresssymptoms of allergic rhinitis, and suppress weight gain. The histamineH₄ receptor is the most recently identified histamine receptor and hasbeen characterized as a distinct histamine receptor. The histamine H₄receptor has been found in a number of mammalian tissues and has beendetermined to modulate a number of physiological processes, includingimmunological function.

By use of histamine H₄ ligands in animal disease models as well as in invitro and ex vivo studies, the histamine H₄ receptor has beendemonstrated to play an important role in various physiological andpathophysiological processes. Separately, in experiments with histamineH₄ deficient (knock out) animals and cells and tissues from suchhistamine H₄ deficient animals, the histamine H₄ receptor has beendemonstrated to play an important role in various physiological andpathophysiological processes. Examples of diseases and disorders wherehistamine H₄ receptors have been found to play an important roleinclude, for example, asthma, allergy, rheumatoid arthritis, andinflammation.

The activity of histamine H₄ receptors can be modified or regulated bythe administration of histamine H₄ receptor ligands. The ligands candemonstrate antagonist, inverse agonist, or partial agonist activity.

Histamine H₄ ligands in different structural classes have been reviewedin (Schwartz, Expert Opinion in Therapeutic Patents (2003) vol. 13, pp.851-865). It would be beneficial to provide additional compoundsdemonstrating H₄ receptor-modulating activity that can be incorporatedinto pharmaceutical compositions useful for therapeutic methods.

SUMMARY OF THE INVENTION

The invention is directed to macrocyclic spiro derivatives, particularlymacrocyclic spiro pyrimidine derivatives, as well as compositionscomprising and methods of using the same. Compounds of the inventionhave the formula (I):

or a pharmaceutically acceptable salt, ester, amide, prodrug thereof,wherein

G¹ is selected from oxygen, sulfur, S(O), S(O)₂, NR⁸ and alkylene;

G² is selected from oxygen, sulfur, S(O), S(O)₂, NR⁸, and alkylene;

wherein each carbon of the alkylene groups of G¹ and G² may beoptionally substituted with one or more groups selected from acyl,acyloxy, alkenyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonyl,alkyl, alkylcarbonyl, alkylcycloalkyl, alkylsulfonyl, alkylthio,alkynyl, amido, carboxy, cyano, cyanoalkyl, cycloalkoxyalkyl,cycloalkyl, fluorine, fluoroalkoxy, fluoroalkyl, fluorocycloalkyl,fluorocycloalkylalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxy,hydroxyalkyl, mercapto, nitro, and oxo;

provided that only one of G¹ or G² can be oxygen, sulfur, S(O), S(O)₂ orNR⁸;

G⁴ is CH₂ or a bond;

R¹ is selected from hydrogen, NH₂, —NH(acyl), —NH(alkyl), —N(alkyl)₂,—NH(C═O)aryl, —NH-alkylene(NR⁸R⁹), —NH(C═O)-alkylene(NR⁸R⁹),—NR⁸(C═O)NR⁸R⁹, —NH-alkylene-heteroaryl, —NHOH, —NHOCH₃,—O-alkylene(NR⁸R⁹), alkoxy, alkoxycarbonyl, alkyl, carboxy,—(C═O)—(NR⁸R⁹), —(C═O)—NH-alkylene(NR⁸R⁹), cyano, cyanoalkyl,cycloalkyl, fluoroalkyl, fluorocycloalkyl, hydroxyalkyl, and piperazine;

R⁶ at each occurrence is independently selected from hydrogen,alkoxyalkyl, alkyl, alkylcycloalkyl, cyanoalkyl, cycloalkoxyalkyl,cycloalkyl, fluoroalkyl, fluorocycloalkyl, fluorocycloalkylalkyl, andhydroxyalkyl;

R⁷ at each occurrence is independently is selected from alkoxyalkyl,fluoroalkyl, fluorocycloalkyl, fluorocycloalkylalkyl, and hydroxyalkyl;

R⁸ and R⁹ are each independently selected from acyl, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcycloalkyl, alkylsulfonyl,amido, aryl, cyanoalkyl, cycloalkoxyalkyl, cycloalkyl, fluoroalkyl,fluorocycloalkyl, fluorocycloalkylalkyl, heteroaryl, heterocycle,hydrogen, formyl, hydroxy, and hydroxyalkyl;

R¹⁰ and R¹¹ taken together are alkylene, —OCH₂CH₂O—, —OCH₂CH₂CH₂O—,—CH₂CH₂OCH₂CH₂—, or

A¹ is a group of structure A² or A³,

wherein A² is

and A³ is selected from

wherein G³ is O, S, S(O), S(O)₂;n is 1, 2, or 3;m is 0, 1, or 2;wherein each carbon atom of groups A¹ may be optionally substituted withone or more groups selected from acyl, acyloxy, alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylcycloalkyl, alkylsulfonyl, alkylthio, alkynyl, amido, carboxy,cyano, cyanoalkyl, cycloalkoxyalkyl, cycloalkyl, fluorine, fluoroalkoxy,fluoroalkyl, fluorocycloalkyl, fluorocycloalkylalkyl, formyl,haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, andnitro.

Another aspect of the invention relates to pharmaceutical compositionscomprising compounds of the invention. Such compositions can beadministered in accordance with a method of the invention, typically aspart of a therapeutic regimen for treatment or prevention of conditionsand disorders related to histamine H₄ receptor activity.

In addition, compounds of the invention can have the formula (I) andalso demonstrate an ability to modulate histamine H₄ receptor activity.In this aspect, the invention relates to a method of modulatinghistamine H₄ receptor activity. The method is useful for treating orpreventing conditions and disorders related to histamine H₄ receptormodulation in mammals. More particularly, the method is useful fortreating or preventing conditions and disorders related to the immunesystem involving inflammatory processes, autoimmune disease, and also innervous system activities involved in pain, such as inflammatory pain,and non-inflammatory pain, especially neuropathic pain. Accordingly, thecompounds and compositions of the invention are useful as a medicamentfor treating or preventing histamine H₄ receptor modulated disease.Examples of such conditions and disorders include, but are not limitedto, asthma, allergy, allergic dermatitis, rheumatoid arthritis,inflammation, inflammatory bowel disease, colitis, ulcerative colitis,Crohn's disease, psoriasis, psoriatic arthritis, osteoarthritis, eczema,hives, multiple sclerosis, auto-immune encephalomyelitis, auto-immunedisease, scleroderma, lupus, dermatitis, atopic dermatitis, rhinitis,allergic rhinitis, chronic obstructive pulmonary disease, septic shock,acute respiratory distress syndrome, cancer, pruritis, itching, pain,inflammatory pain, hyperalgesia, inflammatory hyperalgesia, migraine,cancer pain, osteoarthritis pain, post-surgical pain, non-inflammatorypain, neuropathic pain, sub-categories of neuropathic pain includingperipheral neuropathic pain syndromes, chemotherapy-induced neuropathy,complex regional pain syndrome, HIV sensory neuropathy, neuropathysecondary to tumor infiltration, painful diabetic neuropathy, phantomlimb pain, postherpetic neuralgia, postmastectomy pain, trigeminalneuralgia, central neuropathic pain syndromes, central poststroke pain,multiple sclerosis pain, Parkinson disease pain, and spinal cord injurypain.

Another aspect of the invention relates to the use of the compounds ofthe invention (compounds of formula (I)) in combination with histamineH₁ antagonists (such as loratidine), histamine H₂ antagonists (such asnizatidine), histamine H₃ antagonists (such as ABT-239 or GSK-189254),modulators of TNF-α (such as adalimumab), anti-inflammatorycorticocosteroids (such as dexamethasone), 5-lipoxygenase inhibitors(such as zileuton), leukotriene antagonists (such as zafirlukast) orLTB4 antagonists, with NSAIDS (such as ibuprofen) including, COX-2inhibitors (such as celecoxib), with β-adrenergic receptor agonists suchas salmeterol, anti-nociceptive opiate agonists (such as morphine),anti-nociceptive alpha adrenergic agonists (such as dexmedetomidine),TRPV1 antagonists, nicotinic agonists such as ABT-418 or(1S,5S)-3-(5,6-dichloro-3-pyridinyl)-3,6-diazobicyclo[3.2.0]heptane,CB-1 agonists, CB-2 agonists, P2X7 antagonists, metabotropic glutamatereceptor antagonists, an anticonvulsant such as gabapentin orpregabilin, or a tricyclic antidepressant such as amitriptyline. Thecompounds, compositions comprising the compounds, and methods fortreating or preventing conditions and disorders by administering thecompounds, are further described herein.

DETAILED DESCRIPTION OF THE INVENTION Definition of Terms

Certain terms as used in the specification are intended to refer to thefollowing definitions, as detailed below.

The term “acyl” as used herein means an alkyl group, as defined herein,appended to the parent molecular moiety through a carbonyl group, asdefined herein. Representative examples of acyl include, but are notlimited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl,and 1-oxopentyl.

The term “acyloxy” as used herein means an acyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of acyloxy include, but are not limited to,acetyloxy, propionyloxy, and isobutyryloxy.

The term “alkenyl” as used herein means a straight or branched chainhydrocarbon containing from 2 to 10 carbons, and preferably 2, 3, 4, 5,or 6 carbons, and containing at least one carbon-carbon double bond.Representative examples of alkenyl include, but are not limited to,ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl,5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkoxy” as used herein means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy.

The term “alkoxyalkoxy” as used herein means an alkoxy group, as definedherein, appended to the parent molecular moiety through another alkoxygroup, as defined herein. Representative examples of alkoxyalkoxyinclude, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy,2-methoxyethoxy, and methoxymethoxy.

The term “alkoxyalkyl” as used herein means an alkoxy group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of alkoxyalkyl include, butare not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl,and methoxymethyl.

The term “alkoxycarbonyl” as used herein means an alkoxy group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkoxycarbonyl include, but are not limited to, methoxycarbonyl,ethoxycarbonyl, and tert-butoxycarbonyl.

The term “alkoxyimino” as used herein means an alkoxy group, as definedherein, appended to the parent molecular moiety through a —C(═NH)—group, which also is defined as an imino group. Representative examplesof alkoxyimino include, but are not limited to, methoxy(imino),ethoxy(imino) and tert-butoxy(imino).

The term “alkoxysulfonyl” as used herein means an alkoxy group, asdefined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein. Representative examples ofalkoxysulfonyl include, but are not limited to, methoxysulfonyl,ethoxysulfonyl, and propoxysulfonyl.

The term “alkyl” as used herein means a straight or branched chainhydrocarbon containing from 1 to 10 carbon atoms, and preferably 1, 2,3, 4, 5, or 6 carbons. Representative examples of alkyl include, but arenot limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl,3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl,n-octyl, n-nonyl, and n-decyl.

The term “alkylene” means a divalent group derived from a straight orbranched chain hydrocarbon of from 1 to 10 carbon atoms. Representativeexamples of alkylene include, but are not limited to, —CH₂—, —CH(CH₃)—,—C(CH₃)₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and —CH₂CH(CH₃)CH₂—.

The term “alkylamino” as used herein means an alkyl group, as definedherein, appended to the parent molecular moiety through an NH group.Representative examples of alkylamino include, but are not limited to,methylamino, ethylamino, isopropylamino, and butylamino.

The term “alkylcarbonyl” as used herein means an alkyl group, as definedherein, appended to the parent molecular moiety through a carbonylgroup, as defined herein. Representative examples of alkylcarbonylinclude, but are not limited to, methylcarbonyl, ethylcarbonyl,isopropylcarbonyl, n-propylcarbonyl, and the like.

The term “alkylcycloalkyl” as used herein means an alkyl group, asdefined herein, appended to the parent molecular moiety through acycloalkyl group, as defined herein. Representative examples ofalkylcycloalkyl include, but are not limited to, 4-ethylcyclohexyl,3-methylcyclopentyl, 2-isopropylcyclopropyl and the like.

The term “alkylsulfonyl” as used herein means an alkyl group, as definedherein, appended to the parent molecular moiety through a sulfonylgroup, as defined herein. Representative examples of alkylsulfonylinclude, but are not limited to, methylsulfonyl and ethylsulfonyl.

The term “alkylthio” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through a sulfur atom.Representative examples of alkylthio include, but are not limited,methylthio, ethylthio, tert-butylthio, and hexylthio.

The term “alkynyl” as used herein means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms, and preferably2, 3, 4, or 5 carbons, and containing at least one carbon-carbon triplebond. Representative examples of alkynyl include, but are not limitedto, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and1-butynyl.

The term “amido” as used herein means an amino, alkylamino, ordialkylamino group appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples of amidoinclude, but are not limited to, aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl, and ethylmethylaminocarbonyl.

The term “amino” as used herein means an —NH₂ group.

The term “aryl,” as used herein, means phenyl, a bicyclic aryl, or atricyclic aryl. The bicyclic aryl is naphthyl, a phenyl fused to acycloalkyl, or a phenyl fused to a cycloalkenyl. The bicyclic aryl ofthe invention must be attached to the parent molecular moiety throughany available carbon atom contained within the phenyl ring.Representative examples of the bicyclic aryl include, but are notlimited to, dihydroindenyl, indenyl, naphthyl, dihydronaphthalenyl, andtetrahydronaphthalenyl. The tricyclic aryl is anthracene orphenanthrene, a bicyclic aryl fused to a cycloalkyl, a bicyclic arylfused to a cycloalkenyl, or a bicyclic aryl fused to a phenyl. Thetricyclic aryl is attached to the parent molecular moiety through anycarbon atom contained within a phenyl ring. Representative examples oftricyclic aryl ring include, but are not limited to, azulenyl,dihydroanthracenyl, fluorenyl, and tetrahydrophenanthrenyl.

The carbon atoms of the aryl groups of this invention are substitutedwith hydrogen or are optionally substituted with substituentsindependently selected from acyl, acyloxy, alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl,alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, amido, carboxy, cyano,cycloalkyl, fluoroalkoxy, formyl, haloalkoxy, haloalkyl, halogen,hydroxy, hydroxyalkyl, mercapto, nitro, alkylthio, —NR⁸R⁹,(NR⁸R⁹)carbonyl, —SO₂NR⁸R⁹, —NR⁸(C═O)NR⁸R⁹, —NR⁸(C═O)Oalkyl, andN(R⁸)SO₂(R⁹). Where the aryl group is a phenyl group, the number ofsubstituents is 0, 1, 2, 3, 4, or 5. Where the aryl group is a bicyclicaryl, the number of substituents is 0, 1, 2, 3, 4, 5, 6, or 7. Where thearyl group is a tricyclic aryl, the number of substituents is 0, 1, 2,3, 4, 5, 6, 7, 8, or 9.

The term “arylalkyl” as used herein means an aryl group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of arylalkyl include, but arenot limited to, benzyl, 2-phenylethyl and 3-phenylpropyl.

The term “carbonyl” as used herein means a —C(═O)— group.

The term “carboxy” as used herein means a —CO₂H group.

The term “cyano” as used herein means a —CN group, attached to theparent molecular moiety through the carbon.

The term “cyanoalkyl” as used herein means a —CN group attached to theparent molecular moiety through an alkyl group. Representative examplesof “cyanoalkyl” include, but are not limited to, 3-cyanopropyl, and4-cyanobutyl.

The term “cyanophenyl” as used herein means a —CN group appended to theparent molecular moiety through a phenyl group, including, but notlimited to, 4-cyanophenyl, 3-cyanophenyl, and 2-cyanophenyl.

The term “cycloalkyl” as used herein means a saturated cyclichydrocarbon group containing from 3 to 10 carbons. Examples ofcycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. C₃-C₅ cycloalkyl in particular refers to asaturated cyclic hydrocarbon group containing from 3 to 5 carbons, forexample, cyclopropyl, cyclobutyl, and cyclopentyl.

The term “cycloalkenyl” as used herein means a cyclic hydrocarbon groupcontaining from 3 to 10 carbons, containing 1 or 2 carbon-carbon doublebonds. Examples of cycloalkenyl include cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclohexenyl, cycloheptentyl, and cyclooctenyl.

Each of the carbon atoms of the cycloalkyl or cycloalkenyl groups of theinvention is substituted with 0, 1, or 2 substituents selected fromacyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkyl, alkylcarbonyl,alkylsulfonyl, alkynyl, amido, carboxy, cyano, fluoroalkoxy, formyl,haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, oxo,nitro, alkylthio, —NR⁸R⁹, (NR⁸R⁹)carbonyl, —SO₂N(R⁸)(R⁹),—NR⁸(C═O)NR⁸R⁹, —NR⁸(C═O)Oalkyl, and —N(R⁸)SO₂(R⁹), wherein, R⁸ and R⁹are defined herein.

The term “cycloalkoxy” as used herein, means a cycloalkyl group, asdefined herein, appended to the parent molecular moiety through anoxygen atom. Representative examples of cycloalkoxy include, but are notlimited to, cyclohexyloxy and cyclopropoxy.

The term “cycloalkoxyalkyl” as used herein means a cycloalkoxy group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, wherein alkyl is as defined herein. Representative examples ofcycloalkoxylalkyl include, but are not limited to, cyclobutoxymethyl,cyclopentyloxymethyl, 2-(cyclopentyloxy)ethyl and cyclohexyloxymethyl.

The term “cycloalkylcarbonyl” as used herein means a cycloalkyl group,as defined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofcycloalkylcarbonyl include, but are not limited to, cyclopropylcarbonyl,cyclopentylcarbonyl, cyclohexylcarbonyl, and cycloheptylcarbonyl.

The term “cycloalkylalkyl” as used herein means a cycloalkyl group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of cycloalkylalkylinclude, but are not limited to, cyclopropylmethyl, cyclopentylmethyl,cyclohexylmethyl, and cycloheptylmethyl. (C₃-C₅ cycloalkyl)alkyl inparticular refers to a saturated cyclic hydrocarbon group containingfrom 3 to 5 carbons, for example, cyclopropyl, cyclobutyl, andcyclopentyl, appended to the parent molecular moiety through an alkylgroup.

The term “dialkylamino” as used herein means two independent alkylgroups, as defined herein, appended to the parent molecular moietythrough a nitrogen atom. Representative examples of dialkylaminoinclude, but are not limited to, dimethylamino, diethylamino,ethylmethylamino, and butylmethylamino.

The term “fluoro” or “fluorine” as used herein means —F.

The term “fluoroalkyl” as used herein means at least one fluoro group,appended to the parent molecular moiety through an alkyl group, asdefined herein. Representative examples of fluoroalkyl include, but arenot limited to, fluoromethyl, difluoromethyl, trifluoromethyl,pentafluoroethyl, and 2,2,2-trifluoroethyl.

The term “fluoroalkoxy” as used herein means at least one fluoro group,appended to the parent molecular moiety through an alkoxy group, asdefined herein. Representative examples of fluoroalkoxy include, but arenot limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy,pentafluoroethoxy, and 2,2,2-trifluoroethoxy.

The term “fluorocycloalkyl” as used herein means a fluoro as definedherein, attached to a cycloalkyl moiety, attached to the parentmolecular moiety through the cycloalkyl group. Representative examplesof fluorocycloalkyl include, but are not limited to, 4-fluorocyclohexyl,2,2-difluorocyclobutyl and the like.

The term “fluorocycloalkylalkyl” as used herein means a fluorocycloalkylgroup as defined herein, attached to the parent molecular moiety throughan alkyl group. Representative examples of fluorocycloalkylalkylinclude, but are not limited to, (4-fluorocyclohexyl)methyl,(2,2-difluorocyclobutyl)methyl and the like.

The term “formyl” as used herein means a —C(O)H group.

The term “halo” or “halogen” as used herein means Cl, Br, I, or F.

The term “haloalkoxy” as used herein means at least one halogen, asdefined herein, appended to the parent molecular moiety through analkoxy, as defined herein. Representative examples of haloalkoxyinclude, but are not limited to, 2-fluoroethoxy, trifluoromethoxy, andpentafluoroethoxy.

The term “haloalkyl” as used herein means at least one halogen, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of haloalkyl include,but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl,pentafluoroethyl, and 2-chloro-3-fluoropentyl.

The term “heteroaryl”, as used herein, refers to an aromatic ringcontaining one or more heteroatoms independently selected from nitrogen,oxygen, and sulfur. Such rings can be monocyclic or bicyclic as furtherdescribed herein.

The terms “monocyclic heteroaryl” or “5- or 6-membered heteroaryl ring”,as used herein, refer to 5- or 6-membered aromatic rings containing atleast one heteroatom independently selected from nitrogen, oxygen, andsulfur. The 5-membered ring contains two double bonds; such a ring maycontain one, two, three or four nitrogen atoms, or may contain one ortwo nitrogen atoms and one oxygen atom, or may contain one or twonitrogen atoms and one sulfur atom, or may contain one oxygen atom, ormay contain one sulfur atom. The 6-membered ring contains three doublebonds, or alternatively, the 6-membered ring may contain 2 double bondswithin the ring when the ring is substituted with an oxo group.Furthermore, the 6-membered ring may contain one, two, three or fournitrogen atoms, or may contain one or two nitrogen atoms and one oxygenatom, or may contain one or two nitrogen atoms and one sulfur atom, ormay contain one or two nitrogen atoms and one sulfur atom, or maycontain one or two nitrogen atoms and or one oxygen atom. The 5- or6-membered heteroaryl is connected to the parent molecular moietythrough any carbon atom or any substitutable nitrogen atom containedwithin the monocyclic heteroaryl ring. Representative examples of 5- to6-membered heteroaryl rings include, but are not limited to, furyl,imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiadiazolyl,thiadiazolonyl, thiadiazinonyl, oxadiazolyl, oxadiazolonyl,oxadiazinonyl, thiazolyl, thienyl, triazinyl, triazolyl, triazolyl,pyridazinonyl, pyridonyl, and pyrimidinonyl.

The term “bicyclic heteroaryl” or “8- to 12-membered bicyclic heteroarylring”, as used herein, refers to an 8-, 9-, 10-, 11-, or 12-memberedbicyclic aromatic ring wherein one or more of the atoms of the ring havebeen replaced with at least one heteroatom selected from oxygen, sulfur,and nitrogen. The bicyclic heteroaryl of the invention maybe attached tothe parent molecular moiety through any available carbon atom ornitrogen atom contained within the heteroaryl ring. Representativeexamples of bicyclic heteroaryl rings include indolyl, benzothienyl,benzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl,benzoisothiazolyl, benzoisoxazolyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, phthalazinyl, pteridinyl, purinyl,naphthyridinyl, cinnolinyl, thieno[2,3-d]imidazole,1,5-dihydro-benzo[b][1,4]diazepin-2-on-yl, and pyrrolopyrimidinyl.

Heteroaryl groups of the invention, whether monocyclic or bicyclic, aresubstituted with hydrogen, or optionally substituted with substituentsindependently selected from acyl, acyloxy, alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl,alkyl, alkylcarbonyl, alkylsulfonyl, alkylthio, alkynyl, amido, carboxy,cyano, cycloalkyl, fluoroalkoxy, formyl, haloalkoxy, haloalkyl, halogen,hydroxy, hydroxyalkyl, mercapto, nitro, oxo, —NR⁸R⁹, (NR⁸R⁹)carbonyl,—SO₂N(R⁸)(R⁹), —NR⁸(C═O)NR⁸R⁹, —NR⁸(C═O)Oalkyl, and —N(R⁸)SO₂(R⁹).Monocyclic heteroaryl or 5- or 6-membered heteroaryl rings aresubstituted with 0, 1, 2, 3, 4, or 5 substituents. Bicyclic heteroarylor 8- to 12-membered bicyclic heteroaryl rings are substituted with 0,1, 2, 3, 4, 5, 6, 7, 8, or 9 substituents. Heteroaryl groups of theinvention may be present as tautomers.

The term “heterocycle” or “heterocyclic” as used herein, means amonocyclic heterocycle or a bicyclic heterocycle. The monocyclicheterocycle is a 3, 4, 5, 6 or 7 membered ring containing at least oneheteroatom independently selected from the group consisting of O, N, andS. The 3- or 4-membered ring contains 1 heteroatom selected from thegroup consisting of O, N and S. The 5-membered ring contains zero or onedouble bond and one, two or three heteroatoms selected from the groupconsisting of O, N and S. The 6- or 7-membered ring contains zero, one,or two double bonds provided that the ring, when taken together with asubstituent, does not tautomerize with a substituent to form an aromaticring and one, two, three, or four heteroatoms selected from the groupconsisting of O, N and S. The monocyclic heterocycle is connected to theparent molecular moiety through any carbon atom or any nitrogen atomcontained within the monocyclic heterocycle. Representative examples ofmonocyclic heterocycle include, but are not limited to, azetidinyl,azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl,1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl,isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl,morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl,piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl,pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl,thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone),thiopyranyl, and trithianyl. The bicyclic heterocycle is a monocyclicheterocycle fused to a phenyl group, a monocyclic heterocycle fused to acycloalkyl, a monocyclic heterocycle fused to a cycloalkenyl, or amonocyclic heterocycle fused to a monocyclic heterocycle. The bicyclicheterocycle is connected to the parent molecular moiety through anycarbon atom or any nitrogen atom contained within the monocyclicheterocycle. Representative examples of bicyclic heterocycle include,but are not limited to, 1,3-benzodioxolyl, 1,3-benzodithiolyl,2,3-dihydro-1,4-benzodioxinyl, 2,3-dihydro-1-benzofuranyl,2,3-dihydro-1-benzothienyl, 2,3-dihydro-1H-indolyl,hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl,tetrahydro-1H-pyrrolo[3,4-b]pyridin-6(2H,7H,7aH)-yl, and1,2,3,4-tetrahydroquinolinyl.

The non-aromatic heterocycles of the invention substituted withhydrogen, or optionally substituted with 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9substituents independently selected from acyl, acyloxy, alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl,alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, amido, carboxy, cyano,cycloalkyl, fluoroalkoxy, formyl, haloalkoxy, haloalkyl, halogen,hydroxy, hydroxyalkyl, mercapto, nitro, alkylthio, —NR⁸R⁹,(NR⁸R⁹)carbonyl, —SO₂N(R⁸)(R⁹), —NR⁸(C═O)NR⁸R⁹, —NR⁸(C═O)Oalkyl, and—N(R⁸)SO₂(R⁹).

The term “hydroxy” or “hydroxyl” as used herein means an —OH group.

The term “hydroxyalkyl” as used herein means at least one hydroxy group,as defined herein, appended to the parent molecular moiety through analkyl group, as defined herein. Representative examples of hydroxyalkylinclude, but are not limited to, hydroxymethyl, 2-hydroxyethyl,2-methyl-2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and2-ethyl-4-hydroxyheptyl.

The term “hydroxy-protecting group” means a substituent which protectshydroxyl groups against undesirable reactions during syntheticprocedures. Examples of hydroxy-protecting groups include, but are notlimited to, methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl,2-(trimethylsilyl)ethoxymethyl, benzyl, triphenylmethyl,2,2,2-trichloroethyl, t-butyl, trimethylsilyl, t-butyldimethylsilyl,t-butyldiphenylsilyl, methylene acetal, acetonide benzylidene acetal,cyclic ortho esters, methoxymethylene, cyclic carbonates, and cyclicboronates. Hydroxy-protecting groups are appended onto hydroxy groups byreaction of the compound that contains the hydroxy group with a base,such as triethylamine, and a reagent selected from an alkyl halide,alkyl triflate, trialkylsilyl halide, trialkylsilyl triflate,aryldialkylsilyltriflate, or an alkylchloroformate, CH₂I₂, or adihaloboronate ester, for example with methyl iodide, benzyl iodide,triethylsilyltriflate, acetyl chloride, benzyl chloride, ordimethylcarbonate. A protecting group also may be appended onto ahydroxy group by reaction of the compound that contains the hydroxygroup with acid and an alkyl acetal.

The term “imino” as defined herein means a —C(═NH)— group.

The term “mercapto” as used herein means a —SH group.

The term “(NR⁸R⁹)” as used herein means both an R⁸ and R⁹ group, whereinR⁸ and R⁹ are each as defined for compounds of formula (I), are appendedto the parent molecular moiety through a nitrogen atom. The “(NR⁸R⁹)” isappended to the parent molecular moiety through the nitrogen atom.

The term “(NR⁸R⁹)alkyl” as used herein means an —NR⁸R⁹ group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of (NR⁸R⁹)alkyl include, butare not limited to, 2-(methylamino)ethyl, 2-(dimethylamino)ethyl,2-(amino)ethyl, 2-(ethylmethylamino)ethyl, and the like.

The term “(NR⁸R⁹)carbonyl” as used herein means an —NR⁸R⁹ group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples of(NR⁸R⁹)carbonyl include, but are not limited to, aminocarbonyl,(methylamino)carbonyl, (dimethylamino)carbonyl,(ethylmethylamino)carbonyl, and the like.

The term “—NR⁸(C═O)Oalkyl” as used herein means an amino group attachedto the parent moiety to which is further appended a R⁸ group as definedherein, and a (C═O), i.e. carbonyl, group to which is appended anOalkyl, i.e. alkoxy, group. Representative examples of —NR⁸(C═O)Oalkylinclude, but are not limited to, methyl N-methylcarbamate, tert-butylN-methylcarbamate, and the like.

The term “—NR⁸(C═O)NR⁸R⁹” as used herein means an amino group attachedto the parent moiety to which is further appended a R⁸ group as definedherein, and a (C═O)NR⁸R⁹, i.e. (NR⁸R⁹)carbonyl, as defined herein.Representative examples of —NR⁸(C═O)NR⁸R⁹ include, but are not limitedto, methylurea, phenyl urea, and the like.

The term “(NR⁸R⁹)sulfonyl” as used herein means a —NR⁸R⁹ group, asdefined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein. Representative examples of(NR⁸R⁹)sulfonyl include, but are not limited to, aminosulfonyl,(methylamino)sulfonyl, (dimethylamino)sulfonyl and(ethylmethylamino)sulfonyl.

The term “—N(R⁸)SO₂(R⁹)” as used herein means an amino group attached tothe parent moiety to which is further appended with a R⁸ group asdefined herein, and a SO₂ group to which is appended an (R⁹) group asdefined herein. Representative examples of —N(R⁸)SO₂(R⁹) include, butare not limited to, N-methylmethanesulfonamide.

The term “—SO₂(NR⁸R⁹)” as used herein means a NR⁸R⁹ group appended tothe parent moiety through a sulfonyl group. Representative examples of—SO₂(NR⁸R⁹) include, but are not limited to (dimethylamino)sulfonyl andN-cyclohexyl-N-methylsulfonyl.

The term “nitro” as used herein means a —NO₂ group.

The term “nitrogen protecting group” as used herein means those groupsintended to protect a nitrogen atom against undesirable reactions duringsynthetic procedures. Nitrogen protecting groups comprise carbamates,amides, N-benzyl derivatives, and imine derivatives. Preferred nitrogenprotecting groups are acetyl, benzoyl, benzyl, benzyloxycarbonyl (Cbz),formyl, phenylsulfonyl, pivaloyl, tert-butoxycarbonyl (Boc),tert-butylacetyl, trifluoroacetyl, and triphenylmethyl (trityl).Nitrogen-protecting groups are appended onto primary or secondary aminogroups by reacting the compound that contains the amine group with base,such as triethylamine, and a reagent selected from an alkyl halide, analkyl triflate, a dialkyl anhydride, for example as represented by analkyl anhydride (alkyl-C═O)₂O, a diaryl anhydride, for example asrepresented by (aryl-C═O)₂O, an acyl halide, an alkylchloroformate, oran alkylsulfonylhalide, an arylsulfonylhalide, or halo-CON(alkyl)₂, forexample acetyl chloride, benzoyl chloride, benzyl bromide,benzyloxycarbonyl chloride, formylfluoride, phenylsulfonyl chloride,pivaloyl chloride, (tert-butyl-O—C═O)₂O, trifluoroacetic anhydride, andtriphenylmethylchloride.

The term “oxo” as used herein means (═O).

The term “sulfonyl” as used herein means a —S(O)₂— group.

Antagonists are ligands that block receptor activation by an agonist. Inthe case of the histamine H₄ receptor, a histamine H₄ receptorantagonist blocks activation of the histamine H₄ receptor by a histamineH₄ receptor agonist such as the endogenous agonist ligand histamine.Inverse agonists are ligands that block receptor activation moregenerally: they block intrinsic activation of a receptor that occurs inthe absence of an agonist activation by an agonist, and also blockreceptor activation by an agonist. Partial agonists are ligands thatbind to receptors but only partially activate the receptor; in so doing,partial agonists compete with full agonists and block full activation ofthe receptor. In the case of the histamine H₄ receptor, the endogenousagonist histamine is a full agonist.

Compounds of the Invention

Compounds of the invention can have the formula (I) as described in theSummary of the Invention. In addition, certain embodiments of theinvention further describe compounds of formula (I):

In compounds of formula (I), G¹ is oxygen, sulfur, S(O), S(O)₂, NR⁸ oran alkylene group, for example a hydrocarbon chain of 1, 2, 3, 4, 5, 6,7, 8, 9, or 10 carbons. Preferably, G¹ is —CH₂CH₂— or —CH₂—.

G² is selected from alkylene, oxygen, sulfur, S(O), S(O)₂, NR⁸;

wherein each carbon of the alkylene groups of G¹ and G² may beoptionally substituted with one or more groups selected from acyl,acyloxy, alkenyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonyl,alkyl, alkylcarbonyl, alkylcycloalkyl, alkylsulfonyl, alkylthio,alkynyl, amido, carboxy, cyano, cyanoalkyl, cycloalkoxyalkyl,cycloalkyl, fluorine, fluoroalkoxy, fluoroalkyl, fluorocycloalkyl,fluorocycloalkylalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxy,hydroxyalkyl, mercapto, nitro, and oxo;

provided that only one of G¹ or G² can be oxygen, sulfur, S(O), S(O)₂ orNR⁸.

Preferably, G² is —CH₂— or —CH₂CH₂—.

G⁴ is CH₂ or a bond.

Preferably, G⁴ is a bond.

R¹ is selected from hydrogen, NH₂, —NH(acyl), —NH(alkyl), —N(alkyl)₂,NH(C═O)aryl, —NH-alkylene(NR⁸R⁹), —NH(C═O)-alkylene(NR⁸R⁹),—NH-alkylene-heteroaryl, —NHOH, —NHOCH₃, —O-alkylene(NR⁸R⁹), alkoxy,alkoxycarbonyl, alkyl, carboxy, —(C═O)—(NR⁸R⁹),—(C═O)—NH-alkylene(NR⁸R⁹), cyano, cyanoalkyl, cycloalkyl, fluoroalkyl,fluorocycloalkyl, hydroxyalkyl, and piperazine. Preferably, R¹ is NH₂.

R¹⁰ and R¹¹ taken together are alkylene, —OCH₂CH₂O—, —OCH₂CH₂CH₂O—,—CH₂CH₂OCH₂CH₂—, or

Preferably, R¹⁰ and R¹¹ taken together are —CH₂CH₂CH₂CH₂— or—CH₂CH₂CH₂CH₂CH₂—.

A¹ is a group of structure A² or A³

wherein A² is:

and A³ is selected from

wherein G³ is O, S, S(O), S(O)₂;n is 1, 2, or 3;m is 0, 1, or 2; andwherein each carbon atom of groups A¹ may be optionally substituted withone or more groups selected from acyl, acyloxy, alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylcycloalkyl, alkylsulfonyl, alkylthio, alkynyl, amido, carboxy,cyano, cyanoalkyl, cycloalkoxyalkyl, cycloalkyl, fluorine, fluoroalkoxy,fluoroalkyl, fluorocycloalkyl, fluorocycloalkylalkyl, formyl,haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, andnitro.

Specific groups contemplated for A¹ have the structure:

Suitable groups for G¹, G², G⁴, R¹, R¹⁰, R¹¹, and A¹ in compounds offormula (I) are each independently selected. The described embodimentsof the present invention may be combined. Such combination iscontemplated and within the scope of the present invention. For example,it is contemplated that preferred groups for any of G¹, G², G⁴, R¹, R¹⁰,R¹¹, and A¹ can be combined with groups defined for any other of G¹, G²,G⁴, R¹, R¹⁰, R¹¹, and A¹, whether or not such group is preferred.

There also exists a pharmaceutical composition comprising a compound offormula (I) and a pharmaceutically acceptable carrier.

Representative examples of the invention are further described herein inthe Examples. In particular, preferred embodiments contemplated as partof the invention also include4′-(piperazin-1-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine,(R)-4′-(3-(methylamino)pyrrolidin-1-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine,4′-(3-(methylamino)azetidin-1-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine,and(R)-4′-(3-aminopyrrolidin-1-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine.The practice of assigning names to chemical compounds from structures,and of assigning chemical structures from given chemical names, is wellknown to those of ordinary skill in the art.

Compounds of the invention may exist as stereoisomers, whereinasymmetric or chiral centers are present. These stereoisomers are “R” or“S” depending on the configuration of substituents around the chiralcarbon atom. The terms “R” and “S” used herein are configurations asdefined in IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, in Pure Appl. Chem., 1976, 45: 13-30. The inventioncontemplates various stereoisomers and mixtures thereof, and these arespecifically included within the scope of this invention. Stereoisomersinclude enantiomers and diastereomers, and mixtures of enantiomers ordiastereomers. Individual stereoisomers of compounds of the inventionmay be prepared synthetically from commercially available startingmaterials which contain asymmetric or chiral centers or by preparationof racemic mixtures followed by resolution well-known to those ofordinary skill in the art. These methods of resolution are exemplifiedby (1) attachment of a mixture of enantiomers to a chiral auxiliary,separation of the resulting mixture of diastereomers byrecrystallization or chromatography and optional liberation of theoptically pure product from the auxiliary as described in Furniss,Hannaford, Smith, and Tatchell, “Vogel's Textbook of Practical OrganicChemistry”, 5th edition (1989), Longman Scientific & Technical, EssexCM20 2JE, England, or (2) direct separation of the mixture of opticalenantiomers on chiral chromatographic columns or (3) fractionalrecrystallization methods.

Compounds of the invention may exist as cis or trans isomers, whereinsubstituents on a ring may be attached in such a manner that they are onthe same side of the ring (cis) relative to each other, or on oppositesides of the ring relative to each other (trans). For example,cyclobutanes and cyclohexanes may be present in the cis or transconfiguration, and may be present as a single isomer or a mixture of thecis and trans isomers. Individual cis or trans isomers of compounds ofthe invention may be prepared synthetically from commercially availablestarting materials using selective organic transformations, or preparedin single isomeric form by purification of mixtures of the cis and transisomers. Such methods are well-known to those of ordinary skill in theart and may include separation of isomers by recrystallization orchromatography.

It should be understood that the compounds of the invention may possesstautomeric forms, as well as geometric isomers, and that these alsoconstitute an aspect of the invention. It is also understood that thecompounds of the invention may exist as isotopomers, wherein atoms mayhave different weights; for example, hydrogen, deuterium and tritium, or¹²C, ¹¹C and ¹³C, or ¹⁹F and ¹⁸F.

Methods of the Invention

Compounds and compositions of the invention are useful for modulatingthe histamine H₄ receptor, particularly by histamine H₄ receptorantagonism, partial agonism, or inverse agonism. In particular, thecompounds and compositions of the invention can be used for treating andpreventing disorders modulated by the histamine H₄ receptor. Typically,such disorders can be ameliorated by modulating histamine H₄ receptorsin a mammal, preferably by administering a compound or composition ofthe invention, either alone or in combination with another active agent,for example, as part of a therapeutic regimen.

Certain substituted macrocyclic spiro pyrimidine compounds, includingbut not limited to those specified as compounds of the invention,demonstrate the ability to affect histamine H₄ receptor activity, and inparticular demonstrate histamine H₄ receptor antagonism. Such compoundscan be useful for the treatment and prevention of a number of histamineH₄ receptor-mediated diseases or conditions. Compounds of the inventiondemonstrate such activity and have the formula (I), as previouslydefined herein.

There is also disclosed a method of treating a mammal having a conditionwhere modulation of histamine H₄ receptor activity is of therapeuticbenefit, said method comprising administering to a subject having orsusceptible to said disorder with a therapeutically effective amount ofa compound of the formula (I), or a pharmaceutically acceptable salt,ester, amide, or prodrug thereof, as presented in the Summary of theInvention and Detailed Description sections of the present Invention.

There is also disclosed a method of treating a mammal having a conditionwhere modulation of histamine H₄ receptor activity is of therapeuticbenefit. The method comprises administering to a subject having orsusceptible to said disorder a therapeutically effective amount of acompound of the formula (I), as previously defined.

The method is particularly beneficial when the condition or disorder isasthma, allergy, allergic dermatitis, rheumatoid arthritis,inflammation, inflammatory bowel disease, colitis, ulcerative colitis,Crohn's disease, psoriasis, psoriatic arthritis, osteoarthritis, eczema,hives, multiple sclerosis, auto-immune encephalomyelitis, auto-immunedisease, scleroderma, lupus, dermatitis, atopic dermatitis, rhinitis,allergic rhinitis, chronic obstructive pulmonary disease, septic shock,acute respiratory distress syndrome, cancer, pruritis, itching, pain,inflammatory pain, hyperalgesia, inflammatory hyperalgesia, migraine,cancer pain, non-inflammatory pain, neuropathic pain, sub-categories ofneuropathic pain including peripheral neuropathic pain syndromes,chemotherapy-induced neuropathy, complex regional pain syndrome, HIVsensory neuropathy, neuropathy secondary to tumor infiltration, painfuldiabetic neuropathy, phantom limb pain, postherpetic neuralgia,postmastectomy pain, trigeminal neuralgia, central neuropathic painsyndromes, central poststroke pain, multiple sclerosis pain, Parkinsondisease pain, or spinal cord injury pain.

In particular, it is particularly beneficial to administer compounds offormula (I) for the prevention and treatment of asthma.

It also is particularly beneficial to administer compounds of formula(I) for the prevention and treatment of inflammation.

It also is particularly beneficial to administer compounds of formula(I) for the prevention and treatment of pain. More particularly, it isbeneficial to administer compounds of formula (I) for prevention andtreatment of inflammatory pain. Compounds of formula (I) alsodemonstrate therapeutic benefit in treating and preventingnon-inflammatory pain. In particular, compounds of formula (I) can beadministered for treatment and prevention of neuropathic pain.

As an important consequence of the ability of the compounds of theinvention to modulate the effects of histamine H₄ receptors in cells,the compounds described for the method of the invention can affectphysiological processes in humans and animals. In this way, thecompounds and compositions of formula (I) are useful for treating andpreventing diseases and disorders modulated by histamine H₄ receptors.Typically, treatment or prevention of such diseases and disorders can beeffected by modulating the histamine H₄ receptors in a mammal by theadministration of a compound or composition of the invention, eitheralone or in combination with another active agent as part of atherapeutic regimen.

Particularly preferred are compounds of formula (I) for the method,include, but are not limited to,4′-(piperazin-1-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine,(R)-4′-(3-(methylamino)pyrrolidin-1-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine,4′-(3-(methylamino)azetidin-1-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine,and(R)-4′-(3-aminopyrrolidin-1-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine.

Compounds of formula (I) can be administered to a subject having such adisorder or susceptible to such disorders in a therapeutically effectiveamount. The compounds are particularly useful for a method of treating amammal having a condition where modulation of histamine H₄ receptoractivity is of therapeutic benefit, wherein the method is accomplishedby administering a therapeutically effective amount of a compound offormula (I) to a subject having, or susceptible to, such a disorder.

Compounds useful for the method of the invention include, but are notlimited to, those specified in the examples and possess an affinity forthe histamine H₄ receptor. Such compounds therefore may be useful forthe treatment and prevention of diseases or conditions related tohistamine H₄ modulation. Examples of such diseases or conditions are,for example, asthma, allergy, allergic dermatitis, rheumatoid arthritis,inflammation, inflammatory bowel disease, colitis, ulcerative colitis,Crohn's disease, psoriasis, psoriatic arthritis, osteoarthritis, eczema,hives, multiple sclerosis, auto-immune encephalomyelitis, auto-immunedisease, scleroderma, lupus, dermatitis, atopic dermatitis, rhinitis,allergic rhinitis, chronic obstructive pulmonary disease, septic shock,acute respiratory distress syndrome, cancer, pruritis, itching, pain,inflammatory pain, hyperalgesia, inflammatory hyperalgesia, migraine,cancer pain, non-inflammatory pain, neuropathic pain, sub-categories ofneuropathic pain including peripheral neuropathic pain syndromes,chemotherapy-induced neuropathy, complex regional pain syndrome, HIVsensory neuropathy, neuropathy secondary to tumor infiltration, painfuldiabetic neuropathy, phantom limb pain, postherpetic neuralgia,postmastectomy pain, trigeminal neuralgia, central neuropathic painsyndromes, central poststroke pain, multiple sclerosis pain, Parkinsondisease pain, and spinal cord injury pain. The ability of histamine H₄receptor modulators, and consequently the compounds of the invention, toprevent or treat such disorders is demonstrated by evidence and examplesfound in references which follow.

Histamine H₄ receptor ligands have utility in treatment of a number ofdiseases and conditions, including asthma, allergy, allergic dermatitis,rheumatoid arthritis, inflammation, inflammatory bowel disease, colitis,ulcerative colitis, Crohn's disease, psoriasis, psoriatic arthritis,osteoarthritis, eczema, hives, multiple sclerosis, auto-immuneencephalomyelitis, auto-immune disease, scleroderma, lupus, dermatitis,atopic dermatitis, rhinitis, allergic rhinitis, chronic obstructivepulmonary disease, septic shock, acute respiratory distress syndrome,cancer, pruritis, itching, pain, inflammatory pain, hyperalgesia,inflammatory hyperalgesia, migraine, cancer pain, non-inflammatory pain,neuropathic pain, sub-categories of neuropathic pain includingperipheral neuropathic pain syndromes, chemotherapy-induced neuropathy,complex regional pain syndrome, HIV sensory neuropathy, neuropathysecondary to tumor infiltration, painful diabetic neuropathy, phantomlimb pain, postherpetic neuralgia, postmastectomy pain, trigeminalneuralgia, central neuropathic pain syndromes, central poststroke pain,multiple sclerosis pain, Parkinson disease pain, and spinal cord injurypain.

The histamine H₄ receptor, or gene message coding for the histamine H₄receptor (detected as cDNA by reverse transcriptase polymerase chainamplification (RTPCR) of cellular messenger (mRNA)), has been detectedin a number of cells and tissues critically affected in diseaseconditions. For example, the histamine H₄ receptor plays a critical rolein inflammation, in autoimmune disorders such as rheumatoid arthritis,and in disorders of the immune system. For example, the histamine H₄receptor has been detected in cells of the immune system and in organsof the immune system: neutrophils, eosinophils, basophils, dendriticcells, mast cells, bone marrow, thymus, spleen, brain. For examples, seeLiu, et al. Molecular Pharmacology (2001) vol. 59 pp. 420-426; de Esch,et al. Trends in Pharmacological Sciences Vol. 26 No. 9 pp. 462-469;Oda, et al. Journal of the Pharmocological Society (2005) vol. 98, pp.319-322; Zhu, et al. Molecular Pharmacology, (2001), v. 59, pp. 434-441;Gutzmer, et al. Journal of Immunology (2005) vol. 174 pp. 5224-5232;Coge, et al., Biochemical and Biophysical Research Communications (2001)vol. 284, pp. 301-309.

Histamine H₄ receptor is found at high (compared to normal) levels indisease tissues in rheumatoid arthritis, see for example,Grzybowska-Kowalczyk et al., Inflammation Research (2007), 56,Supplement 1, S1-S2; Maslinska, et al. 34^(th) Meeting of the EuropeanHistamine Research Society in Bled, Slovenia 2005 poster number 3;Jablonowska, et al. 35^(th) Meeting of the European Histamine ResearchSociety in Delphi, Greece (May 10-13, 2006) presentation 036; Ikawa, etal. Biol. Pharm. Bull. (2005) vol. 28(10) pp. 2016-2018.

The role of histamine H₄ receptors in allergy, asthma, and allergicairway inflammation is shown by the finding that transgenic mice withouthistamine H₄ receptors are resistant to the development of disease in ananimal model of asthma. The observation that a selective synthetic H₄ligand elicits the same benefit in the asthma model also supports thebenefits of H₄ ligands in treatment of disease. For example, seeDunford, et al. The Journal of Immunology (2006) vol. 176, pp.7062-7070.

General reviews and papers on the role of histamine receptor in diseaseinclude Akdis and Simons, European Journal of Pharmacology (2006) vol.533 pp. 69-76; de Esch, et al., Trends in Pharmacological Sciences Vol.26 No. 9 pp. 462-469; Thurmond, et al., Journal of Pharmacology andExperimental Therapeutics (2004) vol. 309 pp. 404-413; Buckland, et al.,British Journal of Pharmacology (2003) 140, 1117-1127. The utility forhistamine H₄ receptor ligands in cancer is supported by the finding thatthe H₄ receptor has been found expressed on mammary cell carcinomatissues, as reported by Maslinska, et al., 34th Meeting of the EuropeanHistamine Research Society in Bled, Slovenia (May 11-15, 2005)presentation. Histamine H₄ receptor activation was found to exert aproliferative effect in cancer tissues, Cianchi, et al., Clinical CancerResearch (2005) vol. 11 (19) pp. 6807-6815. In gastritis and gastriclesions, histamine H₄ ligands were found to reduce the lesions inducedby administration of indomethacin in vivo: Coruzzi, et al. Jablonowska,et al. 35^(th) Meeting of the European Histamine Research Society inDelphi, Greece (May 10-13, 2006) presentation O44. In colitis, histamineH₄ ligands were found to reduce the lesions induced by administration oftrinitrobenzesulfonic acid in vivo: Varga, et al., European Journal ofPharmacology (2005) vol. 522 pp. 130-138; Fogel, et al., 35^(th) Meetingof the European Histamine Research Society in Delphi, Greece (May 10-13,2006) presentation P32. In itch and pruritis, the benefit of histamineH₄ receptor ligands has been shown by Bell, et al., British Journal ofPharmacology (2004) vol. 142, pp. 374-380.

The invention also relates to use of the compounds of the invention ashistamine H₄ receptor ligands to treat pain, including distinctlydifferent types of pain, including inflammatory pain, chemically inducedpain, pain resulting from surgery, pain resulting from burns, painresulting from osteoarthritis, non-inflammatory pain, and neuropathicpain. The usefulness of histamine H₄ receptor ligands in treating painhas been demonstrated (U.S. patent application Ser. No. 11/863,925;Coruzzi, et al., Eur. J. Pharmacol. 2007, 563, 240-244).

Neuropathic pain is distinct from other types of pain (e.g. inflammatorypain) in that it can develop in response to previous or ongoing tissue,nerve injury, or diabetes, but it persists long after signs of theoriginal injury or damage have disappeared. Neuropathic pain isassociated with allodynia, hyperalgesia, or causalgia (Dworkin ClinicalJournal of Pain (2002) vol. 18(6) pp. 343-9). Allodynia is theperception of pain following a stimulus that would not normally bepainful. Hyperalgesia is an enhanced response to a mildly noxiousstimulus. Causalgia is described as a chronic burning pain that showspersistence in the absence of obvious noxious stimuli.

Neuropathic pain is not well treated with current therapies, andtherefore there is a strong need for methods to treat this particulartype of pain. The topic of neuropathic pain has been reviewed in thescientific literature, for example, Smith, et al., Drug DevelopmentResearch (2001) vol. 54(3), pp. 140-153; Collins and Chessell, ExpertOpinion on Emerging Drugs (2005) vol. 10(1), pp. 95-108; Vinik andMehrabyan, Medical Clinics of North America (2004), vol. 88(4), pp.947-999; Dray, Urban, and Dickenson, Trends in Pharmacological Sciences(1994) vol. 15(6) pp. 190-7; Dworkin, Clinical Journal of Pain (2002)vol. 18(6) pp. 343-9. A number of animal models of neuropathic pain thatcan be used to assess the ability of the compounds of the invention totreat neuropathic pain exist and are further discussed inter alia.Compounds of the invention are effective in treatment of neuropathicpain. Compounds of the invention are also effective in treating othertypes of pain, non-inflammatory pain, post surgical pain, andinflammatory pain.

Neuropathic pain is a description that encompasses more specific namesof pain that are sub-categories of neuropathic pain (Dworkin, ClinicalJournal of Pain (2002) vol. 18(6) pp. 343-9) including peripheralneuropathic pain syndromes, chemotherapy-induced neuropathy, complexregional pain syndrome, HIV sensory neuropathy, neuropathy secondary totumor infiltration, painful diabetic neuropathy, phantom limb pain,postherpetic neuralgia, postmastectomy pain, trigeminal neuralgia,central neuropathic pain syndromes, central poststroke pain, multiplesclerosis pain, Parkinson disease pain, and spinal cord injury pain.

In addition to neuropathic pain, there are other types of pain that arenot inflammatory or not due to ongoing inflammation, includingosteoarthritis pain, cancer pain, and visceral pain. A general review ofanimal models of pain is found in Joshi and Honore, Expert Opinion inDrug Discovery (2004) 1, pp. 323-334.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention can be varied so as to obtain an amountof the active compound(s) that is effective to achieve the desiredtherapeutic response for a particular patient, compositions and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated, and the condition and prior medical historyof the patient being treated. However, it is within the skill of the artto start doses of the compound at levels lower than required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved.

When used in the above or other treatments, a therapeutically effectiveamount of one of the compounds of the invention can be employed in pureform or, where such forms exist, in a pharmaceutically acceptable salt,ester, amide or prodrug form. Alternatively, the compound can beadministered as a pharmaceutical composition containing the compound ofinterest in combination with one or more pharmaceutically acceptablecarriers. The phrase “therapeutically effective amount” of the compoundof the invention means a sufficient amount of the compound to treatdisorders, at a reasonable benefit/risk ratio applicable to any medicaltreatment. It will be understood, however, that the total daily usage ofthe compounds and compositions of the invention will be decided by theattending physician within the scope of sound medical judgment. Thespecific therapeutically effective dose level for any particular patientwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed; andlike factors well known in the medical arts. For example, it is wellwithin the skill of the art to start doses of the compound at levelslower than required to achieve the desired therapeutic effect and togradually increase the dosage until the desired effect is achieved.

For treatment or prevention of disease, the total daily dose of thecompounds of this invention administered to a human or lower animal mayrange from about 5 to about 500 micromoles/kg of body weight. Forpurposes of oral administration, more preferable doses can be in therange of from about 30 to about 500 micromoles/kg body weight. Ifdesired, the effective daily dose can be divided into multiple doses forpurposes of administration; consequently, single dose compositions maycontain such amounts or submultiples thereof to make up the daily dose.

Methods for Preparing Compounds of the Invention

The compounds of the invention can be better understood in connectionwith the following synthetic schemes and methods, which illustrate ameans by which the compounds can be prepared.

Abbreviations which have been used in the descriptions of the schemesand the examples that follow are: Boc for butyloxycarbonyl; DMF forN,N-dimethylformamide; DMSO for dimethyl sulfoxide; dppf for1,1′-bis(diphenylphosphino)ferrocene; EDTA forethylenediaminetetraacetic acid; Et₂O for diethyl ether; EtOAc for ethylacetate; HEK for human embryonic kidney cells; HPLC for high pressureliquid chromatography; MCPBA for 3-chloroperoxybenzoic acid; Me formethyl; MeOH for methanol; Ms for methanesulfonyl; Pd for palladium; tBufor tert-butyl; TEA for triethylamine; TFA for trifluoroacetic acid; THFfor tetrahydrofuran; Tf for trifluoromethanesulfonyl; Ts forpara-toluenesulfonyl; Tris for trishydroxymethylaminomethane; dba fordibenzylidineacetone; DMAP for 4-di(methylamino)pyridine; OAc foracetoxy; Ph for phenyl; HOAc for acetic acid; HMPA forhexamethylphosphoramide; MeI for methyl iodide; rt for “roomtemperature” or ambient temperature suitably ranging 17-30° C. CASnumbers may be used as identifiers of compounds available fromdescriptions reported in the literature or available commercially. CASnumbers are identifier numbers assigned to compounds by the ChemicalAbstracts Service of the American Chemical Society and are well known tothose of ordinary skill in the art.

The compounds of this invention can be prepared by a variety ofsynthetic procedures. Representative procedures are shown in, but arenot limited to, Schemes 1-13.

Compounds of formula (7A²), wherein R¹, R¹⁰, R¹¹, A², G¹, G², and G⁴ aredefined in formula (I), may be prepared as outlined in Scheme 1. Ketonesof formula (1), which are obtained either from commercial sources orsynthesized through the methods outlined herein, when treated with abase such as sodium hydride or butyllithium, followed by treatment witheither a carbonate such as dimethyl carbonate, or a chloroformate suchas ethyl chloroformate, will provide keto-ester containing compounds offormula (2), wherein R is lower alkyl. Compounds of formula (2) whentreated with a compound of formula (3), such as guanidine nitrate, inthe presence of a base such as potassium carbonate under heatedconditions in a solvent such as DMF will provide compounds of formula(4). Compounds of formula (4) can exist as shown in the structure inscheme 1 or in a tautomeric form. Compounds of formula (4) when treatedwith a chlorinating reagent such as but not limited to HCl, with orwithout heating as needed, will provide compounds of formula (5),wherein Y=Cl. Alternatively, compounds of formula (4) may also betreated with reagents such as para-toluenesulfonyl chloride,methylsulfonyl chloride or trifluoromethanesulfonyl chloride in thepresence of a base such as triethylamine in a solvent such as pyridineor chloroform to provide compounds of formula (5) wherein Y=O—SO₂—R′,wherein R′ is lower alkyl, lower fluoroalkyl or aryl. Compounds offormula (5), wherein Y=Cl or —O—SO₂—R′, when treated with compounds offormula (6), wherein (6) contains a primary or secondary nitrogen atomand H is a hydrogen atom on said nitrogen atom, under heated conditionsin the presence or absence of a base such as triethylamine ordiisopropylethylamine, in a solvent such as ethanol, 2-methoxyethanol,toluene or acetonitrile, will provide compounds of formula (7A²).

Compounds of formula (7A²), wherein R¹=H and R¹⁰, R¹¹, A², G¹, G² and G⁴are defined in formula (I), may be prepared by treating a compound offormula (2) with thiourea with heating in the presence of a base such assodium methoxide in a solvent such as methanol, followed by reduction ofthe resulting product using a reagent such as Raney nickel to providecompounds of formula (4) wherein R¹=H. Compounds of formula (4) whereinR¹=H can be treated according to the method above to provide compoundsof formula (7A²) wherein R¹=H.

Compounds of formula (7A²) may be further reacted, according toconditions known to one skilled in the art, so as to alter functionalgroups contained within the compound (for example, the removal of aprotecting group such as Boc or the hydrolysis of an ester group), inorder to generate compounds of the present invention or used within thescope of other schemes described herein.

Compounds of formula (6) that contain two different nitrogen atoms mayselectively react with compounds of formula (5) to provide one isomer offormula (7A²). Such selectivity may be the result of substitution orprotecting groups attached to one of the nitrogen atoms. Alternatively,compounds of formula (6) that contain two different N—H groups may reactwith compounds of formula (5) in a non-selective manner wherein amixture of two different compounds of formula (7A²) is obtained from thereaction. Mixtures of compounds of formula (7A²) are generally separatedby methods known to one skilled in the art, such as silica based columnchromatography, selective recrystallization, or both.

Alternatively, compounds of formula (7A²), which are representative ofcompounds of the present invention wherein R¹, R¹⁰, R¹¹, A², G¹, G², andG⁴ are defined in formula (I), may also be prepared as outlined inScheme 2. Compounds of formula (1) when treated with carbon disulfideand iodomethane in the presence of a base such as but not limited to NaHin a solvent such as but not limited to THF will provide compounds offormula (10). Compounds of formula (10), when treated with a compound offormula (3), wherein R¹ is defined in formula (I), will provide sulfidesof formula (11). Compounds of formula (11), when treated with anoxidizing agent such as MCPBA or Oxone® will provide sulfones of formula(12). Compounds of formula (12), when treated with compounds of formula(6), which contain a primary or secondary amine under heated conditions,in the presence or absence of a base such as triethyl amine ordiisopropylethylamine, in a solvent such as ethanol or 2-methoxyethanol,will provide compounds of formula (7A²), which are representative ofcompounds of the present invention.

Compounds of formula (7A³), wherein R¹, R¹⁰, R¹¹, A³, G¹, G², and G⁴ aredefined in formula (I), may be prepared as outlined in Scheme 3.Alcohols and thiols of formula (13), and alcohols and thiols that alsocontain an amine group wherein the nitrogen atom is protected with asynthetic protecting group such as a butoxycarbonyl group, which areobtained either from commercial sources or synthesized through themethods outlined herein, can be treated with a base such as sodiumhydride, then treated with compounds of formula (5), wherein Y=Cl,p-toluenesulfonyl or SO₂Me, and then heated to provide compounds offormula (7A³). Alternative bases such as potassium tert-butoxide,potassium hydride, and potassium carbonate may also be employed. Moregenerally, alcohols and thiols of formula (13) are described in thescientific literature and may be prepared by those of ordinary skill inthe art of organic synthesis.

Compounds of formula (7A³) may be further reacted, according toconditions known to those of ordinary skill in the art of organicsynthesis, to alter functional groups (for example, the removal of aprotecting group such as Boc or the hydrolysis of an ester group), inorder to generate compounds of the present invention or to be furthertransformed within the scope of other schemes described herein.

Compounds of formula (7), which are representative of compounds of thepresent invention wherein R¹, R¹⁰, R¹¹, A¹, G₂, and G⁴ are as defined informula (I), and G¹ is alkylene, can be prepared as outlined in Scheme4. Treatment of compounds of formula (1a) with p-toluenesulfonymethylchloride in the presence of a base such as t-butyllithium will providecompounds of formula (1), wherein G¹ is alkylene. Further examplesdescribing similar reactions are found in the following reference:Satoh, T.; et al. Tetrahedron 1994, 50, 11839-52. Compounds of formula(1), when treated as outlined in Schemes 1, 2 or 3, will providecompounds of formula (7), which are representative of compounds of thepresent invention wherein G¹ is alkylene.

As outlined in Scheme 5, compounds of formula (6a) may contain two aminegroups. The amine groups of compounds of formula (6a) may be eitherprimary or secondary and can be used directly in Schemes 1 or 2 toprovide compounds of formula (7A²). Alternatively, compounds of formula(6a), which contain two N—H groups, may be treated with an appropriatereagent such as R⁶—X, wherein X is a leaving group such as chlorine,bromine, iodine, mesylate, or triflate, to provide compounds of formula(57), wherein one of the two N—H groups is substituted with R⁶.Substituting compounds of formula (57) for compounds of formula (6) inthe procedures outlined in Scheme 1 or Scheme 2 will provide compoundsof formula (7A²), which are representative of the present invention.

Furthermore, compounds of formula (6a) that contain two amine groups maybe treated with a reagent which will introduce a nitrogen protectinggroup (PG¹) on one of the amine groups. Some typical examples of commonnitrogen protecting groups include, but are not limited to, benzyl,tert-butoxycarbonyl, benzyloxycarbonyl, or acetyl. Such groups areintroduced by treating amines of formula (6a) with 1 equivalent of anappropriate reagent such as benzyl bromide, di-tert-butyl dicarbonate,benzyl chloroformate, or acetic anhydride, respectively, to providemono-protected diamines of formula (58). Mono-amine protected compoundsof formula (58) can be further treated with an appropriate reagent suchas R⁶—X, wherein R⁶ is defined in formula (I) and X is a leaving groupsuch as chlorine, bromine, iodine, mesylate, or triflate, to providecompounds of formula (59). Compounds of formula (59) can be deprotectedto provide compounds of formula (57), which can then be used to replacecompounds of formula (6) in the procedures outlined in Scheme 1 andScheme 2 to provide compounds of formula (7A²), which are representativeof compounds of the present invention. Common conditions used for thedeprotection of compounds of formula (59) to provide compounds offormula (57) include, but are not limited to, the following: catalytichydrogenation (e.g. in the presence of palladium-on-carbon in a solventsuch as ethanol under an atmosphere of hydrogen); acidic conditions(e.g. treatment with aqueous hydrochloric acid); or basic hydrolysis(e.g. treatment with aqueous sodium hydroxide and heat).

Alternatively, mono-protected diamines of formula (58) may be treatedwith an appropriate aldehyde or ketone under reductive aminationconditions to provide diamines of formula (59). Conditions commonly usedfor reductive amination include treatment of an amine (58) with analdehyde or ketone in the presence of NaBH₃CN or NaBH(OAc)₃.

Mono-protected compounds of formula (58) can be treated with a secondprotecting group (PG²) to provide di-protected compounds of formula(60). In di-protected compounds of formula (60), it is preferred thatthe choice of protecting groups is such that the protecting group PG¹can be removed selectively without removing PG². Selective deprotectionof PG¹ from compounds of formula (60) provides compounds of formula(61). Mono-protected compounds of formula (61) can be treated with anappropriate reagent such as R⁶—X, wherein R⁶ is as defined in formula(I) and X is a leaving group such as chlorine, bromine, iodine,mesylate, or triflate, to provide compounds of formula (62).Alternatively, mono-protected compounds of formula (61), when treatedwith an appropriate aldehyde or ketone under reductive aminationconditions, will provide compounds of formula (62). Compounds of formula(62) can be deprotected to provide compounds of formula (57).

Compounds of formula (7), which are representative of compounds of thepresent invention wherein R¹, R¹⁰, R¹¹, G¹, G², G⁴, and A¹ are definedin formula (I), may be prepared as outlined in Scheme 6. Esters offormula (2), prepared as described in the above schemes, can be treatedwith an excess of urea and heated at 150-190° C. to provide compounds offormula (69). Compounds of formula (69) can exist as shown in thestructure in Scheme 6 or in a tautomeric form. Compounds of formula (69)can be treated with POCl₃ with heating to provide compounds of formula(70). Compounds of formula (70) can be treated with compounds of formula(6), wherein (6) contains a primary or secondary nitrogen atom and H isa hydrogen atom on said nitrogen atom, under heated conditions in thepresence or absence of a base such as triethylamine ordiisopropylethylamine, in a solvent such as ethanol, 2-methoxyethanol,toluene, or acetonitrile, to provide a mixture of compounds of formula(71) and formula (72). Alternatively, compounds of formula (13) can betreated with a base such as sodium hydride or potassium carbonate in asolvent such as THF or DMF and then treated with a compound of formula(70) to provide a mixture of compounds of formula (71) and formula (72).Compounds of formula (71) and formula (72) can be separated by methodsknown to those skilled in the art, such as chromatography on silica gelor selective crystallization. Compounds of formula (72) can be reactedwith a compound of formula (73), where R¹ is defined in formula (I), andwhere compound (73) contains an alcohol or a primary or secondarynitrogen atom and H is a hydrogen atom on said oxygen or nitrogen atom,under heated conditions in the presence or absence of a base such astriethylamine, diisopropylethylamine, or sodium hydride, in a solventsuch as ethanol, 2-methoxyethanol, THF, toluene, DMF, or acetonitrile,to provide compounds of formula (7).

Compounds of formula (72) can also be treated with a catalyst such asPdCl₂(dppf)-CH₂Cl₂ under an atmosphere of carbon monoxide in thepresence of an alcohol such as methanol in the presence of a base suchas triethylamine while heating to provide compounds of formula (7),wherein R¹ is —(C═O)OR, wherein R is lower alkyl. Compounds of formula(7), wherein R¹ is —(C═O)OR, can be treated with an aqueous base such as1 M sodium hydroxide in the presence of a solvent such as methanol toprovide compounds of formula (7), wherein R¹ is —(C═O)OH. Compounds offormula (7), wherein R¹ is —(C═O)OH, can be coupled with amines underconditions known to those of ordinary skill in the art to providecompounds of formula (7), wherein R¹ is selected from —(C═O)—(NR⁸R⁹) and—(C═O)—NH-alkylene(NR⁸R⁹).

Compounds of formula (72) can also be treated with a reagent such aszinc cyanide, in the presence of a catalyst such as Pd(PPh₃)₄, in asolvent such as DMF, with heating, to provide compounds of formula (7),wherein R¹ is cyano.

Compounds of formula (7), which are representative of compounds of thepresent invention wherein R¹⁰, R¹¹, G¹, G², G⁴, and A¹ are defined informula (I), and wherein R¹ is limited to those compounds defined informula (I) that are linked to the pyrimidine via a nitrogen atom, maybe prepared as outlined in Scheme 7. 2-Aminopyrimidines of formula (75)can be prepared as described in the above schemes. 2-Aminopyrimidines offormula (75) can be reacted with reagents such as (alkyl-CO)₂O,Y′-alkyl, alkyl-CO—Y′, aryl-CO—Y′, Y′-alkylene(NR⁸R⁹),Y′—(C═O)-alkylene(NR⁸R⁹), and Y′-alkylene-heteroaryl, wherein Y′ is aleaving group such as Cl, Br, OMs, OTs, or N-hydroxysuccinimide,optionally in the presence of a base such as Hunig's base, sodiumhydride, pyridine or triethylamine, optionally in a solvent such as2-methoxyethanol or DMF, and optionally with heating to providecompounds of formula (7), wherein R¹⁰, R¹¹, G¹, G², G⁴, and A¹ aredefined in formula (I) and R¹ is selected from —NH(acyl), —NH(alkyl),—N(alkyl)₂, —NH(C═O)aryl, —NH-alkylene(NR⁸R⁹), —NH(C═O)-alkylene(NR⁸R⁹),and —NH-alkylene-heteroaryl.

Compounds of formula (13a), wherein A³ is defined in formula (I), arecompounds in which one of the H groups is a proton on an oxygen orsulfur atom and the other H group is a proton on a nitrogen atom of aprimary or secondary amine. Compounds of formula (13a) can be directlyreacted in Scheme 3 of the above in the presence of a strong base suchas sodium hydride to provide compounds of formula (7). Alternatively,compounds of formula (13a) may be treated with an appropriate reagentsuch as R⁶—X, wherein X is a leaving group such as chlorine, bromine,iodine, mesylate, or triflate, to provide compounds of formula (78),wherein the nitrogen atom of (78) is substituted with R⁶. (Scheme 8).Alternatively, mono-protected diamines of formula (13a) may be treatedwith an appropriate aldehyde or ketone under reductive aminationconditions to provide compounds of formula (78). Conditions commonlyused for reductive amination include treatment of an amine (13a) with analdehyde or ketone in the presence of NaBH₃CN or NaBH(OAc)₃.Substituting compounds of formula (78) for compounds of formula (13) inthe procedure outlined in Scheme 3 will provide compounds of formula(7A³), which are representative of the present invention.

Compounds of formula (13a) may be treated with a reagent that willintroduce a nitrogen protecting group (PG¹) on the nitrogen atom of(13a). Some typical examples of common nitrogen protecting groupsinclude, but are not limited to, tert-butoxycarbonyl orbenzyloxycarbonyl, which are introduced by treating compounds of formula(13a) with 1 equivalent of an appropriate reagent such as di-tert-butyldicarbonate or benzyl chloroformate, respectively, to provide compoundsof formula (79), wherein the protecting group (PG¹) is connected to thenitrogen atom. Substituting compounds of formula (79) for compounds offormula (13) in the procedure outlined in Scheme 3 will providecompounds of formula (7A³), wherein the A³ group of formula (7A³)contains a protected nitrogen atom. This protected nitrogen atom ofcompounds of formula (7A³) can be deprotected using conditions known toone skilled in the art, such as catalytic hydrogenation (e.g. in thepresence of palladium-on-carbon in a solvent such as ethanol under anatmosphere of hydrogen) and acidic conditions (e.g. treatment withaqueous hydrochloric acid or with TFA) to provide compounds of formula(7A³), which are representative of the present invention.

Compounds of formula (7), which are representative of compounds of thepresent invention wherein R¹, A¹, G¹, and G² are defined as in formula(I), and wherein G⁴ is a bond and R¹⁰ and R¹¹ taken together are—CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂—,—CH₂CH₂CH₂CH₂CH₂CH₂—, or —CH₂CH₂OCH₂CH₂— can be prepared as outlined inScheme 9. Compounds of formula (80) can be reacted, with or withoutheat, in the presence of a base such as, but not limited to, potassiumtert-butoxide or sodium hydride in a solvent such as THF with compoundsof formula (81), wherein Y′ is chloro, bromo, or iodo, to affordcompounds of formula (1). Such reactions are known to those of ordinaryskill in the art. Compounds of formula (1), when reacted as outlined inSchemes 1, 2, or 3, will provide compounds of formula (7), which arerepresentative of compounds of the present invention.

Compounds of formula (7), which are representative of compounds of thepresent invention wherein R¹, A¹, and G¹ are defined as in formula (I),and wherein G² is alkylene, G⁴ is CH₂, and R¹⁰ and R¹¹ taken togetherare —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂—, or—CH₂CH₂CH₂CH₂CH₂CH₂—, can be prepared as outlined in Scheme 10.Compounds of formula (82), wherein Y′ is chloro, bromo, or iodo, can bereacted with organobis(cuprates) of formula (83) to yield compounds offormula (1). Such reactions have been well-documented in the literature(Wender, et al, J. Am. Chem. Soc. 1988, 110, 2218-2223, and referencescited therein). Compounds of formula (1), when reacted as outlined inSchemes 1, 2, or 3, will provide compounds of formula (7), which arerepresentative of compounds of the present invention.

Compounds of formula (87), wherein R¹, A¹, G¹, and G⁴ are defined as informula (I), and wherein G² is alkylene and Gs is —CH₂CH₂— or—CH₂CH₂CH₂—, can be prepared as shown in Scheme 11. Compounds of formula(84) can be reacted with diols of formula (85), under Dean-Starkconditions and in the presence of para-toluenesulfonic acid, to affordcompounds of formula (86). Such reactions are well-known to those ofordinary skill in the art. Processing compounds of formula (86)according to Schemes 1, 2, or 3 (substituting compounds of formula (86)for compounds of formula (1)) will then afford compounds of formula(87).

Compounds of formula (7), wherein R¹, A¹, R¹⁰, and R¹¹ are defined as informula (I), and wherein G⁴ is a bond, G² is alkylene, and G¹=O, S, NR⁸,or NR^(a), wherein R^(a) is hydrogen, an alkyl group, or a nitrogenprotecting group such as Boc, alkylsulfonyl, arylsulfonyl, or phosphate,can be prepared as outlined in Scheme 12. Dialkylation via heating ofcompounds of formula (88) with compounds of formula (81), wherein Y′ isa leaving group such as iodo, bromo, or chloro, in the presence of abase such as sodium hydride, in a solvent such as dioxane, can affordcompounds of formula (89). Neat treatment of compounds of formula (89)with gaseous hydrogen bromide at ambient temperature, followed byreaction of the purified product with diazomethane in a solvent such asether at 0° C., can result in compounds of formula (90). Heating ofcompounds of formula (91) with a base such as sodium methoxide inmethanol, followed by treatment with compounds of formula (90) andsubsequent heating, can afford compounds of formula (92). Heating ofcompounds of formula (92) with a base such as sodium hydride in asolvent such as benzene then can yield compounds of formula (93).(Similar reaction sequences can be found in the literature: e.g., Baas,et al., Tetrahedron 1966, 22, 285-291.) Processing of compounds offormula (93) according to the procedures outlined in Scheme 1, 2, or 3(substituting compounds of formula (93) for compounds of formula (2))will afford compounds of formula (7), which are representative ofcompounds of the present invention.

Compounds of formula (7), wherein A¹ and R¹ are defined as in formula(I), and wherein G¹ and G² are alkylene, G⁴ is a bond, and R¹⁰ and R¹taken together are —CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂—, or—CH₂CH₂CH₂CH₂CH₂CH₂—, may be prepared according to the reaction sequencedepicted in Scheme 13. Diols of formula (94), available commercially orprepared according to procedures known to those skilled in the art, canbe reacted with trimethoxymethane and a Lewis acid such as borontrifluoride diethyl etherate, in a solvent such as dichloromethane, atmoderately cold temperatures such as −20° C., followed by warming toroom temperature, to afford compounds of formula (95). Such pinacolrearrangements are well-known to those of ordinary skill in the art.Processing of compounds of formula (95) according to the proceduresoutlined in Schemes 1, 2, or 3 (substituting compounds of formula (95)for compounds of formula (1)) will afford compounds of (7), which arerepresentative of compounds of the present invention.

There are many groups of formulas (6), (6a), (13), (57), (58), (59), and(60) that are available commercially or that can be prepared asdescribed in the scientific literature of synthetic organic chemistry.Non-exhaustive examples of diamine and aminoalcohol reagents for thesynthesis of compounds of formula (I) are provided in Table 1, alongwith product compounds that may be produced by application of themethods in the Schemes described above (Scheme 1 through Scheme 13).

TABLE 1 Prospective Examples of synthetic intermediate groups, andProduct Compounds that may be prepared by the methods described inSchemes 1-13. Commercial Source or Literature, or Patent Group CAS #Reference Product from group 2-Methyl-2,6- Diazaspiro[3.4] octane135380-30-2 WO2004056784 A1

7-Methyl-2,7- diazaspiro[3,5] nonane 135380-50-6 Frohlich, Johannes, etal. Heterocycles (1994), 37(3), 1879-91.

2,7-Diazaspiro [3.5]nonane-2- carboxylic acid, 1,1- dimethylethyl ester236406-55-6 WO2005040159 A1

2-(Phenylmethyl)- 2,7-Diazaspiro [3.6]decane 270257-44-8 JP2001039950 A2

2-(Phenylmethyl)- 2,7-Diazaspiro [3.6]decane 270257-44-8 JP2001039950 A2

1-(Phenylmethyl)- 1,7-diazaspiro [4.4]nonane 128244-01-9 Culbertson, T.P., et al. Journal of Medicinal Chemistry (1990), 33(8), 2270-5.

1-(Phenylmethyl)- 1,7-diazaspiro [4.4]nonane 128244-01-9 Culbertson, T.P., et al. Journal of Medicinal Chemistry (1990), 33(8), 2270-5.

2,7-Diazaspiro [4.4]nonane 175-96-2 Culbertson, T. P., et al. Journal ofMedicinal Chemistry (1990), 33(8), 2270-5.

1-(Phenylmethyl)- 1,7-diazaspiro [4.5]decane 867009-85-6 WO2005097794 A1

1-(Phenylmethyl)- 1,7-diazaspiro [4.5]decane 867009-85-6 WO2005097794 A1

2-Ethyl-2,8- Diazaspiro[4.5] decane 64097-83-2 Sueess, Rudolf. HelveticaChimica Acta (1977), 60(5), 1650-6

2,8-Diazaspiro [4.5]decane-8- carboxylic acid, 1,1- dimethylethyl ester236406-39-6 US2006019985 A1

(R)-1,8-Diazaspiro [5.5]undecane 151746-68-8 Zhu, Jieping; et al.Journal of Organic Chemistry (1993), 58(23), 6451-6

(R)-1,8-Diazaspiro [5.5]undecane 151746-68-8 Zhu, Jieping; et al.Journal of Organic Chemistry (1993), 58(23), 6451-6

2,8-Diazaspiro [5.5]undecane 180-50-7 US2005084446 A1

3,9-Diazaspiro [5.5]undecane- 3-carboxylic acid, 1,1- dimethylethylester 173405-78-2 WO2005040167 A1

2,5-Diazabicyclo [2.2.0]hexane 186-07-2 Krivdin, L. B.; et al. RussianJournal of Organic Chemistry (Translation of Zhurnal OrganicheskoiKhimii) (2003), 39(5), 698-704

6-(Phenylmethyl)- 2,6-diazabicyclo [3.2.0]heptane 851526-88-0US2005101602 A1

6-(Phenylmethyl)- 2,6-diazabicyclo [3.2.0]heptane 851526-88-0US2005101602 A1

tert-Butyl 3,7- diazabicyclo [4.2.0]octane-3- carboxylate 885271-67-0MILESTONE PharmTec LLC 100 Jersey Avenue Building D, Box D-4 NewBrunswick, NJ 08901 USA www.milestone pharmtech.com cat # 6M-0032

tert-Butyl 3,7- diazabicyclo [4.2.0]octane-7- carboxylate 885271-73-8MILESTONE PharmTec LLC cat # 6M-0030

,8-Diazabicyclo [4.2.0]octane-8- carboxylic acid, 1,1- dimethylethylester 848591-80-0 US2005101602 A1

,8-Diazabicyclo [4.2.0]octane-8- carboxylic acid, 1,1- dimethylethylester 848591-80-0 US2005101602 A1

Octahydro-pyrrolo [3,2-b]pyrrole 5839-99-6 U.S. Pat. No. 2,932,650

Hexahydro-pyrrolo [3,4-b]pyrrole- 1-carboxylic acid tert-butyl ester185693-02-1 ANICHEM LLC 7 Deer Park Drive Suite M6 Monmouth Junction, NJ08852 www.anichem llc.com catalog # A21583

Hexahydro-pyrrolo [3,4-b]pyrrole- 1-carboxylic acid tert-butyl ester185693-02-1 ANICHEM LLC cat # A21583

1H-Pyrrolo[3,2- c]pyridine, octahydro-1- methyl-, dihydrochloride172281-71-9 U.S. Pat. No. 5,442,044 A

1H-Pyrrolo[2,3- c]pyridine-1- carboxylic acid, octahydro-, 1,1-dimethylethyl ester 169750-88-3 WO9510519A1

1H-Pyrrolo[2,3- c]pyridine-1- carboxylic acid, octahydro-, 1,1-dimethylethyl ester 169750-88-3 WO9510519A1

Octahydro-6- (phenylmethyl)- 1H-pyrrolo[3,4- b]pyridine 128740-14-7TYGER (Aagile Labs Division of Tyger Scientific) 324 Stokes Ave. Ewing,NJ 08638 USA cat #B64518

Octahydro-6- (phenylmethyl)- 1H-pyrrolo[3,4- b]pyridine 128740-14-7TYGER (Aagile Labs Division of Tyger Scientific) 324 Stokes Ave. Ewing,NJ 08638 USA cat #B64518

5H-Pyrrolo[3,4- c]pyridine-5- carboxylic acid, octahydro-, 1,1-dimethylethyl ester 351370-99-5 TYGER (Aagile Labs Division of TygerScientific) 324 Stokes Ave. Ewing, NJ 08638 USA) cat # B64520

Octahydro-2- (phenylmethyl)- 1H-pyrrolo[3,4- c]pyridine 351370-98-4TYGER (Aagile Labs Division of Tyger Scientific) 324 Stokes Ave. Ewing,NJ 08638 USA) cat # B64521

Pyrrolo[3,4- c]azepine-2(1H)- carboxylic acid, octahydro-5-(phenylmethyl)-, 1,1- dimethylethyl ester 236406-58-9 WO9940070A1

Pyrrolo[3,4- c]azepine-2(1H)- carboxylic acid, octahydro-5-(phenylmethyl)-, 1,1- dimethylethyl ester 236406-58-9 WO9940070A1

Pyrrolo[3,4- d]azepine-2(1H)- carboxylic acid, octahydro-6-(phenylmethyl)-, 1,1- dimethylethyl ester 801253-06-5 WO2004103992 A1

Pyrrolo[3,4- d]azepine-2(1H)- carboxylic acid, octahydro-6-(phenylmethyl)-, 1,1- dimethylethyl ester 801253-06-5 WO2004103992 A1

(4aS,8aS)-1,5- Naphthyridine, decahydro-1- (phenylmethyl)- 574001-72-2Li, Xiaolin; et al. Journal of Organic Chemistry (2003), 68(14),5500-5511.

(4aR,8aR)-1,5- Naphthyridine, decahydro-1- methyl- 381227-92-5 Li,Xiaolin, et al. Journal of Organic Chemistry (2003), 68(14), 5500-5511.

(4aR,8aR)-1,6- Naphthyridine- 6(2H)- carboxylic acid, octahydro-1-(phenylmethyl)-, 1,1- dimethylethyl ester 616875-95-7 Kobashi, Seiichi;et al. Yakugaku Zasshi (2003), 123(5), 337-347.

(4aR,8aR)-1,6- Naphthyridine- 6(2H)- carboxylic acid, octahydro-1-(phenylmethyl)-, 1,1- dimethylethyl ester 616875-95-7 Kobashi, Seiichi,et al. Yakugaku Zasshi (2003), 123(5), 337-347.

Decahydro-6- methyl-1,6- naphthyridine 135037-28-4 MicroChemistryBuilding Blocks MicroChemistry Ltd., Kosygina St. 4, Moscow, 119993;Russia; Email: sale@mch.ru; Web: http://www.mch.ru cat # mch- bb-200311276

trans- Decahydro-1,7- Naphthyridine 13623-82-0 Hanus, Vladimir; et al.Organic Mass Spectrometry (1984), 19(9), 459-60.

trans- Decahydro-1,7- Naphthyridine 13623-82-0 Hanus, Vladimir; et al.Organic Mass Spectrometry (1984), 19(9), 459-60.

2,7-Naphthyridine- 2(1H)- carboxylic acid, octahydro-, 1,1-dimethylethyl ester 885270-18-8 MILESTONE PharmTec LLC cat # 6M-0007

8a-Ethyldecahydro- copyrine 873999-52-1 Iselin, B. M.; et al. Journal ofthe American Chemical Society (1954), 76 3220-2.

decahydro-1H- Pyrido[3,2-c]azepine 344460-81-7 Linden, Anthony; et al.Acta Crystallographica, Section C: Crystal Structure Communications(2001), C57(6), 764-766.

Decahydro-1H- Pyrido[3,2-c]azepine 344460-81-7 Linden, Anthony; et al.Acta Crystallographica, Section C: Crystal Structure Communications(2001), C57(6), 764-766.

Octahydro-3- isobutyl- pyrrolo[1,2- a]pyrazine 718631-71-1 ChemstepProduct List 20 Avenue Victor Hugo; Carbon Blanc, 33560; France; Email:info@chemstep. com; Web: http://www. chemstep.com cat # 71454

Octahydro-1- methyl- pyrrolo[1,2- a]pyrazine 155206-39-6 WO2006048750 A2

Octahydro-6- methyl- pyrrolo[1,2- a]pyrazine 22177-06-6 Ponomarev, A.A.; Set al. Metody Polucheniya Khimicheskikh Reaktivov i Preparativ(1967), (17), 5-6

Octahydro-6- methyl-2H- Pyrido[1,2- a]pyrazine 5762-99-2 ChemstepProduct List cat # 70166

Octahydro-pyrido [1,2-a]pyrazine 4430-75-5 Oakwood Products Catalog cat# 032054

Octahydro-1H- Pyrrolo[1,2-a] [1,4]diazepine 109324-83-6 MicroChemistryBuilding Blocks cat # mch-bb- 2003 13717

Decahydro-pyrazino [1,2-a]azepine 49633-80-9 Oakwood Products 1741 OldDunbar Rd.; West Columbia, SC, 29172; USA; Email: sales@fluorochemusa.com; Web: http://www. oakwoodchemical. com Catalog cat # 032087

Octahydro-1H- Cyclopentapyrazine 154393-81-4 Chemstep Product List cat #53753

Decahydro- quinoxaline 90410-24-5 MicroChemistry Building Blocks cat #mch-bb- 2003 11269

Decahydro-2- methyl-quinoxaline, dihydrochloride 114062-34-9 Maffei,Silvio; et al. Gazzetta Chimica Italiana (1958), 88 556-63.

Octahydro-3,3,7,7- tetramethyl-5- diazocine 17288-14-1 Kemp, D. S.; etal. Journal of Organic Chemistry (1979), 44(25), 4473-6.

Octahydro-1- methyl-1,5- diazocine, dihydrobromide 4318-35-8 U.S. Pat.No. 3,247,206

Octahydro-1H- 1,5-diazonine, dihydrochloride 118872-68-7 Stetter, H,; etal. Chemische Berichte (1958), 91 1982-8.

Decahydro-1,6-diazecine, dihydrochloride 118725-33-0 Stetter, H.; et al.Chemische Berichte (1958), 91 1982-8.

Decahydro-1- methyl-1,6- diazecine 68388-04-5 Horner, L.; et al. JustusLiebigs Annalen der Chemie (1978), (9), 1505-17.

Decahydro- 1,5-diazecine 6573-62-2 Bergmann, D. J.; et al. ChemicalCommunications (1999), (14), 1279-1280.

1,6- Diazacycloundecane 294-51-9 Stetter, H,; et al. Chemische Berichte(1958), 91 677-80.

Azetidin-3- ylmethyl-carbamic acid tert-butyl ester 91188-15-7 TYGER(Aagile Labs Division of Tyger Scientific) 324 Stokes Ave. Ewing, NJ08638 USA) cat # A58187

(3-Pyrrolidinyl- methyl)-carbamic acid tert-butyl ester 149366-79-0TYGER (Aagile Labs Division of Tyger Scientific) 324 Stokes Ave. Ewing,NJ 08638 USA) cat # B64504

(3R)-3-((Dimethyl- amino)methyl) pyrrolidine dihydrochloride 859213-49-3WO2005082855 A1

Piperidin-4- ylmethyl- carbamic acid tert-butyl ester 135632-53-0Fluorochem Ltd.; Wesley Street; Old Glossop, Derbyshire, SK13 7RY;United Kingdom; Email: enquiries@ fluorochem.co.uk; Web: http://www.fluorochem.net cat # 17246

Dimethyl-(2- piperidin-4-yl- ethyl)-amine 102308-48-5 MATRIX (MatrixScientific, P O Box 25067; Columbia, SC, 29224-5067 USA; Email:sales@matrix scientific.com; Web: http://www. matrixscientific. com) cat# 020420

3-N-Boc- aminomethyl piperidine 142643-29-6 ALDRICH (Aldrich ChemicalCompany, Inc. 1001 West Saint Paul Avenue Milwaukee, WI 53233 USA) cat #653896

3-(2-Boc- aminoethyl) piperidine 215305-98-9 TYGER (Aagile Labs Divisionof Tyger Scientific) 324 Stokes Ave. Ewing, NJ 08638 USA) cat # B28400

3-Aminomethyl- azetidine-1-carboxylic acid tert-butyl ester 325775-44-8TYGER (Aagile Labs Division of Tyger Scientific) 324 Stokes Ave. Ewing,NJ 08638 USA) cat # A57126

3-Aminomethyl- pyrrolidine-1- carboxylic acid tert-butyl ester270912-72-6 FLROCHEM cat # 11395

Methyl-(1- methyl-pyrrolidin- 3-ylmethyl)-amine 89850-95-3 MATRIXcatalog # 019128

3-Aminoethyl-1- n-cbz-pyrrolidine 811842-07-6 OAKWOOD cat # 11381

1-N-Boc-4- (aminomethyl) piperidine 144222-22-0 ALDRICH cat # 641472

4-(Pyrrolidin-1- ylmethyl)piperidine 683772-11-4 MATRIX cat # 016344

3-(Aminomethyl)-1- N-Boc-piperidine 162167-97-7 OAKWOOD cat # 11388

4-(N-Boc-amino) piperidine 73874-95-0 ALDRICH cat # 540935

4-(2-Boc- aminoethyl)piperidine 165528-81-4 Tyger catalog # B32000

3-Boc- aminopiperidine 172603-05-3 Tyger Scientific Product List cat #B50100

C-(1-Benzyl- piperidin-3-yl)- methylamine 124257-62-1 OAKWOOD cat #30699

(1-Methyl- piperidin-4-yl)- methylamine 7149-42-0 OAKWOOD cat # 32204

(1-Isopropyl- piperidin-3-ylmethyl)- methyl-amine 876716-01-7 MatrixScientific catalog # 19173

(1-Isopropyl- piperidin-4-ylmethyl)- methyl-amine 876716-04-0 MatrixScientific catalog # 19174

4-(1- Azetidinylmethyl)- piperidine, dihydrochloride 864441-51-0WO2005082854 A1

4-(1- Azetidinyl)- piperidine, dihydrochloride 864246-02-6 WO2005082855A1

1-(3- Azetidinyl)- pyrrolidine, bis(trifluoroacetate) 864248-58-8WO2005082854 A1

[1,3′]Bipyrrolidinyl 267241-99-6 Oakwood Products Catalog; catalog #031602

4-(1- Pyrrolidinyl)piperidine 5004-07-9 Aldrich catalog # 437352

3-Pyrrolidin-1- ylmethyl-piperidine 514842-98-9 Oakwood ProductsCatalog; catalog # 032019

3-[2-(1- Pyrrolidinyl) ethyl]piperidine 122373-96-0 DE3726908A1

4-(2-Pyrrolidin-1- yl-ethyl)-piperidine 14759-08-1 Oakwood ProductsCatalog; catalog # 025057

N-Methyl-1- azetidinepropanamine 864246-87-7 WO2005082855 A1

N-Methyl-1- pyrrolidineethanamine 32776-22-0 Aurora Screening Librarycatalog # kec-0001338

Methyl[3- (pyrrolidin-1-yl) propyl]amine 99114-68-8 Surleraux, D. L. N.G.; et al. Journal of Medicinal Chemistry 2005, 48(6), 1965-1973.

N-Methyl-1- pyrrolidinebutanamine 153905-93-2 WO2005082855 A1

2-(Azetidin-1- yl)ethylamine 795299-77-3 WO2006021544 A1

N-(3-Aminopropyl) azetidine 54262-75-8 Murahashi, S.; et al. Journal ofthe American Chemical Society (1983), 105(15), 5002-11.

1-(2-Aminoethyl) pyrrolidine 7154-73-6 ALDRICH catalog # A55357

1-(3-Aminopropyl) pyrrolidine 23159-07-1 Lancaster Synthesis catalog #4739

4-(1-Pyrrolidino) butylamine 24715-90-0 Matrix Scientific catalog # 7650

(1-Benzyl-azetidin- 2-yl)-methylamine 46193-94-6 PharmLab Product Listcatalog # 25-0007

2-(2-Aminoethyl)- 1-methylpyrrolidine 51387-90-7 Aldrich catalog #139505

2-(Aminomethyl)- 1-N-Boc-piperidine 370069-31-1 Fluorochem catalog #11387

(+/−)-2- (Aminomethyl)-1- N-Boc-pyrrolidine 177911-87-4 Fluorochemcatalog # 11393

2-(Aminoethyl)- 1-N-Boc-piperidine 239482-98-5 Fluorochem catalog #11378

2-(3-Amino-propyl)- pyrrolidine-1- carboxylic acid tert-butyl ester887587-47-5 Tyger Scientific Product List catalog # A57685

1,4- Cyclohexanediamine 3114-70-3 TCI-US catalog # C0814

N,N-Dimethyl- cyclohexane- 1,4-diamine 42389-50-4 PharmLab Product Listcatalog # 20-0268

1,3- Cyclohexanediamine 3385-21-5 TCI-US catalog # C0813

1,3- Cyclopentanediamine 73211-32-2 Chemgenx Product List catalog #CX-01566

Benzyl trans-4- aminomethylcyclo- hexylcarbamate 177582-74-0 AMRI FineChemicals catalog # A00095

tert-Butyl trans-4- aminocyclohexyl- methylcarbamate 192323-07-2 AMRIFine Chemicals catalog # A00096

tert-Butyl trans-4- (2-aminoethyl) cyclohexylcarbamate AMRI FineChemicals catalog # A00049

1,3-Cyclohexanebis (methylamine) 2579-20-6 Aldrich catalog # 180467

1,4-Bis(aminomethyl) cyclohexane 2549-93-1 TCI-US catalog # B1083

1-(2-Aminoethyl) pyrrolidine 7154-73-6 Aldrich catalog # A55357

1-(3-Aminopropyl) pyrrolidine 23159-07-1 Acros catalog # 36809

1-(4-Aminobutyl) pyrrolidine 24715-90-0 Matrix catalog # 007650

Methyl-(3-piperidin- 1-yl-propyl)-amine 86010-41-5 Matrix catalog #018963

Methyl-(2-piperidin- 1-yl-ethyl)-amine 41239-39-8 Metrix catalog #018964

4,4′-Bipiperidine dihydrochloride 78619-84-8 Aldrich catalog # 180742

4,4′-Ethylene- dipiperidine dihydrochloride 80997-86-0 Aldrich catalog #214140

2-(1-N-Boc- Aminomethyl- cyclohexyl)- ethylamine 886362-17-0 AstaTechProduct List catalog # 46643

(1-Aminomethyl- cyclopentyl)- carbamic acid tert-butyl ester 889949-09-1Tyger Scientific Product List catalog # A57914

1-Pyrrolidin-1- ylmethyl- cyclohexylamine 876717-44-1 MATRIX catalog #019232

cis-N-methyl-4-(1- pyrrolidinyl)- Cyclohexanamine, dihydrochloride883864-57-1 WO2006040281 A1

trans-3-(1- Pyrrolidinyl)- cyclobutanamine 878156-28-6 WO2006021544 A1

trans-4-(1- Azetidinylmethyl)- cyclohexanamine 878155-27-2 WO2006021544A1

trans-4-(1- Pyrrolidinyl)- cyclohexanamine 734527-26-5 Chemstep ProductList catalog # 43301

1-Methyl-4-(1- pyrrolidinyl)- cyclohexanamine, dihydrochloride412356-30-0 WO2002030890 A1

4-amino-quinuclidine 22766-61-6 Prepared from 4- cyano-quinuclidine (CAS# 26458-78-6), Fluorochem, catalog # 017382. EP0202062A2

4-(aminomethyl)- quinuclidine 67496-78-0 Prepared from 4-cyano-quinuclidine (CAS # 26458-78-6), Fluorochem, catalog # 017382.WO99/21855

(S)-(−)-3-amino- quinuclidine dihydrochloride 119904-90-4 Aldrichcatalog # 415,723

(R)-(+)-3-amino- quinuclidine dihydrochloride 123536-14-1 Aldrichcatalog # 415,715

1-azatricyclo [3.3.1.1^(3.7)]decan- 4r-amine Prepared from 1,4-cyclohexanedione monoethylene acetal (CAS # 4746-97-8), Aldrich catalog# 274879. Becker, D. P. and Flynn, D. L. Synthesis 1992, 1980-82

1-(2-hydroxyethyl) pyrrolidine 2955-88-6 ALDRICH catalog # H29404

N-BOC-D-prolinol 83435-58-9 ALDRICH catalog # 469440

BOC-L-prolinol 69610-40-8 ALDRICH catalog # 446327

(R)-2-hydroxymethyl- piperidine-1- carboxylic acid tert-butyl esterCHEM-IMPEX catalog # 16141

BOC-S-PIP- 2MEOH CHEM-IMPEX catalog # 16146

3-amino- cyclohexanol 6850-39-1 TYGER catalog # A58076

trans-4- aminocyclohexanol 27489-62-9 ALFA catalog # B22365

tert-butyl cis-4- hydroxycyclo- hexylcarbamate 167081-25-6 AMRI catalog# A00071

(cis)-3- aminocyclobutanol ALLWEYS catalog # 11331

(trans)-3- aminocyclobutanol 389890-42-0 ALLWEYS catalog # 11361

N-((3R,4S)-4- methylpyrrolidine- 3-yl)acetamide

(3S,4R)-1- benzyl-1-methyl- pyrrolidine-3-amine

(3S,4R)-1- benzyl-4-methyl- pyrrolidine-3-amine

tert-butyl (3S,4R)-4- (trifluoromethyl) pyrrolidin-3- ylcarbamate168544-95-4 Qun Li, et al., Bioorganic & Medicinal Chemistry Letters(1998), 8(15), 1953-1958.

tert-butyl (3S,4R)-1- (trifluoromethyl) pyrrolidin-3- ylcarbamate

tert-butyl ((3S,4S)-4- (trifluoromethyl) pyrrolidin-3-yl)methylcarbamate 168544-90-9 Qun Li, et al, Bioorganic & MedicinalChemistry Letters (1998), 8(15), 1953-1958.

tert-butyl ((3S,4S)-4- (trifluoromethyl) pyrrolidin-3-yl)methylcarbamate

tert-butyl (3S,5S)-5- methylpyrrolidin- 3-ylcarbamate 139161-75-4 QunLi, et al, Tetrahedron Letters (1995), 36(46), 8391-4

tert-butyl (3S,5S)-5- methylpyrrolidin- 3-ylcarbamate

tert-butyl (3R,5S)-5- methylpyrrolidin- 3-ylcarbamate

tert-butyl (3R,5S)-5- methylpyrrolidin- 3-ylcarbamate

tert-butyl 1-benzyl-3- methylpyrrolidin- 3-ylcarbamate 181417-39-0 T.Yoshida, et al, Chemical & Pharmaceutical Bulletin (1996), 44(7),1376-1386.

tert-butyl 1-benzyl-3- methylpyrrolidin- 3-ylcarbamate

(R)-benzyl 2-((tert- butoxycarbonylamino) methyl)pyrrolidine-1-carboxylate 141774-69-8 R. M. Burch, WO 9203415 A1 (1992)

(R)-benzyl 2-((tert- butoxycarbonylamino) methyl)pyrrolidine-1-carboxylate

tert-butyl (1-benzyl- pyrrolidin-3- yl)methylcarbamate 155497-10-2Matrix 018167

tert-butyl (1-benzyl- pyrrolidin-3- yl)methylcarbamate

N-((1-benzyl- pyrrolidin-3- yl)methyl)ethanamine 91189-07-0 FulcrumB64503

N-((1-benzyl- pyrrolidin-3- yl)methyl)ethanamine

tert-butyl ethyl(((5S)-5- methylpyrrolidin-3- yl)methyl)carbamate

tert-butyl ethyl(((5S)-5- methylpyrrolidin-3- yl)methyl)carbamate

(4S)-1-tert- butyl 3-methyl 4- aminopyrrolidine- 1,3-dicarboxylate362491-96-1 J. Duan, WO 2001070673 A2 (2001)

(4S)-1-tert- butyl 3-methyl 4- aminopyrrolidine- 1,3-dicarboxylate

1-cyclo- propylpiperazine 139256-79-4 Fulcrunm C-1450

1,3- dimethylpiperazine 22317-01-7 G. Steiner, et al, Journal ofMedicinal Chemistry (1986), 29(10), 1877-88.

2-(azetidin-2- yl)ethanamine 90324-66-6 H. Taniyama, et al, YakugakuZasshi (1961), 81 1497-500

2-(azetidin-2- yl)ethanamine

azetidin-2- ylmethanamine 103550-76-1 ABCHEM-INC AB1135

azetidin-2- ylmethanamine

tert-butyl octahydro- 1H-pyrrolo[3,4-b] pyridine-1-carboxylate159877-36-8 Fulcrum B64519

tert-butyl (3aR,4R,7aS)- octahydro-1H- isoindol-4-ylcarbamate181141-44-6 Qun Li, et al, Journal of Medicinal Chemistry (1996),39(16), 3070-3088.

tert-butyl (3aR,4R,7aS)- octahydro-1H- isoindol-4-ylcarbamate

tert-butyl (1R,5S)-3- azabicyclo[3.1.0] hexan-6-ylcarbamate 134575-17-0G. Anquetin, et al, European Journal of Medicinal Chemistry (2006),41(12), 1478-1493.

tert-butyl (1R,5S)-3- azabicyclo[3.1.0] hexan-6-ylcarbamate 134575-17-0G. Anquetin, et al, European Journal of Medicinal Chemistry (2006),41(12), 1478-1493.

tert-butyl (1R)-3-(1- phenylethyl)-3- azabicyclo[3.1.0]hexan-1-ylcarbamate 182075-89-4 M. Takemura, WO 9623782 A1 (1996)

tert-butyl (1R)-2-(1- phenylethyl)-3- azabicyclo[3.1.0]hexan-1-ylcarbamate 182075-89-4 M. Takemura, WO 9623782 A1 (1996)

tert-butyl (1R)-3-(1- phenylethyl)-3- azabicyclo[3.1.0]hexan-1-ylcarbamate 181941-43-5 M. Takemura, WO 9623782 A1 (1996)

tert-butyl (1R)-3-(1- phenylethyl)-3- azabicyclo[3.1.0]hexan-1-ylcarbamate 181941-43-5 M. Takemura, WO 9623782 A1 (1996)

tert-butyl 3- hydroxypyrrolidine- 1-carboxylate 40499-83-0 AldrichP74354

(2S,4R)-tert- butyl-4-hydroxy-2- methylpyrrolidine- 1-carboxylate114676-61-8 Chu, Daniel T,; Li, Qun. U.S. Pat. No. 5,252,747 A (1993)

(3S,5S)-1-benzyl-5- methylpyrrolidin-3-ol 152673-21-7 Qun Li, et al,Tetrahedron Letters (1995), 36(46), 8391-4.

(R)-tert-butyl 2- (hydroxymethyl) azetidine-1- carboxylate 161511-90-6TCI-US B2174

The invention also provides pharmaceutical compositions comprising atherapeutically effective amount of a compound of formula (I) incombination with a pharmaceutically acceptable carrier. The compositionscomprise compounds of the invention formulated together with one or morenon-toxic pharmaceutically acceptable carriers. The pharmaceuticalcompositions can be formulated for oral administration in solid orliquid form, for parenteral, intravenous, subcutaneous, intramuscular,intraperitoneal, intra-arterial, or intradermal injection, or forvaginal, nasal, topical, or rectal administration.

The term “pharmaceutically acceptable carrier”, as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as lactose, glucose and sucrose; starches suchas corn starch and potato starch; cellulose and its derivatives such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil, safflower oil, sesameoil, olive oil, corn oil and soybean oil; glycols; such a propyleneglycol; esters such as ethyl oleate and ethyl laurate; agar; bufferingagents such as magnesium hydroxide and aluminum hydroxide; alginic acid;pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol;and phosphate buffer solutions; as well as other non-toxic compatiblelubricants such as sodium lauryl sulfate and magnesium stearate.Coloring agents, releasing agents, coating agents, sweetening, flavoringand perfuming agents, preservatives, and antioxidants can also bepresent in the composition, according to the judgment of one skilled inthe art of formulations.

The pharmaceutical compositions of this invention can be administered tohumans and other mammals by oral administration or by injection,including by intravenous, subcutaneous, intramuscular, intraperitoneal,intra-arterial, and intradermal injection. The pharmaceuticalcompositions of this invention also can be administered to humans andother mammals topically (as by powders, lotions, ointments, or dropsapplied to the skin), bucally, or by inhalation, as an oral or nasalspray. The pharmaceutical compositions of this invention can beadministered to humans and other mammals intrarectally orintravaginally. The term “parenterally,” as used herein, refers to modesof administration which include intravenous, intramuscular,intraperitoneal, intrasternal, subcutaneous, and intraarticular.

Pharmaceutical compositions for parenteral injection comprisepharmaceutically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propylene glycol,polyethylene glycol, glycerol, and the like, and suitable mixturesthereof), vegetable oils (such as olive oil) and injectable organicesters such as ethyl oleate, or suitable mixtures thereof. Suitablefluidity of the composition may be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservativeagents, wetting agents, emulsifying agents, and dispersing agents.Prevention of the action of microorganisms may be ensured by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, and the like. It may also bedesirable to include isotonic agents, for example, sugars, sodiumchloride and the like. Prolonged absorption of the injectablepharmaceutical form may be brought about by the use of agents that delayabsorption, for example, aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is oftendesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Suspensions, in addition to the active compounds, may contain suspendingagents, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.

If desired, and for more effective distribution, the compounds of theinvention can be incorporated into slow-release or targeted-deliverysystems such as polymer matrices, liposomes, and microspheres. They maybe sterilized, for example, by filtration through a bacteria-retainingfilter or by incorporation of sterilizing agents in the form of sterilesolid compositions, which may be dissolved in sterile water or someother sterile injectable medium immediately before use.

Injectable depot forms are made by forming microencapsulated matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations also are prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic, parenterally acceptablediluent or solvent such as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, one or morecompounds of the invention is mixed with at least one inertpharmaceutically acceptable carrier such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol, and salicylic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay; and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof. In the case of capsules, tablets and pills, the dosageform may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using lactose or milk sugar aswell as high molecular weight polyethylene glycols.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract in a delayedmanner. Examples of materials which can be useful for delaying releaseof the active agent can include polymeric substances and waxes.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating carriers such as cocoa butter,polyethylene glycol or a suppository wax which are solid at ambienttemperature but liquid at body temperature and therefore melt in therectum or vaginal cavity and release the active compound.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. A desired compound ofthe invention is admixed under sterile conditions with apharmaceutically acceptable carrier and any needed preservatives orbuffers as may be required. Ophthalmic formulation, ear drops, eyeointments, powders and solutions are also contemplated as being withinthe scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, animal and vegetable fats, oils,waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, lactose, talc, silicic acid, aluminum hydroxide, calciumsilicates and polyamide powder, or mixtures of these substances. Sprayscan additionally contain customary propellants such aschlorofluorohydrocarbons.

Compounds of the invention may also be administered in the form ofliposomes. As is known in the art, liposomes are generally derived fromphospholipids or other lipid substances. Liposomes are formed by mono-or multi-lamellar hydrated liquid crystals that are dispersed in anaqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes may be used. Thepresent compositions in liposome form may contain, in addition to thecompounds of the invention, stabilizers, preservatives, and the like.The preferred lipids are the natural and synthetic phospholipids andphosphatidylcholines (lecithins) used separately or together.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compound ismixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants, which canbe required. Ophthalmic formulations, eye ointments, powders andsolutions are contemplated as being within the scope of this invention.Aqueous liquid compositions comprising compounds of the invention alsoare contemplated.

The compounds of the invention can be used in the form ofpharmaceutically acceptable salts, esters, or amides derived frominorganic or organic acids. The term “pharmaceutically acceptable salts,esters and amides”, as used herein, refer to carboxylate salts, aminoacid addition salts, zwitterions, esters and amides of compounds offormula (I) which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response, and the like, arecommensurate with a reasonable benefit/risk ratio, and are effective fortheir intended use.

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well-known in the art. The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention or separately by reacting a free base function with a suitableorganic acid.

Representative acids suitable for formation of addition salts bycombination with the compounds of the invention include, but are notlimited to, ascorbic acid, (D)-tartaric acid, (L)-tartaric acid, maleicacid, phosphoric acid, citric acid, hydrochloric acid, sulfuric acid andtrifluoroacetic acid. Other acids include acetic, adipic, aspartic,glutamic, benzoic, benzenesulfonic, 4-methylbenzenesulfonic,camphorsulfonic, propionic, hydrobromic, glucuronic, methanesulfonic,ethanesulfonic, naphthalene sulfonic, lactic, fumaric, oxalic, andsuccinic acid.

Also, the basic nitrogen-containing groups can be quaternized with suchagents as lower alkyl halides such as methyl, ethyl, propyl, and butylchlorides, bromides and iodides; dialkyl sulfates such as dimethyl,diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl,lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkylhalides such as benzyl and phenethyl bromides and others. Water oroil-soluble or dispersible products are thereby obtained.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as the hydroxide,carbonate or bicarbonate of a pharmaceutically acceptable metal cationor with ammonia or an organic primary, secondary or tertiary amine.Pharmaceutically acceptable salts include, but are not limited to,cations based on alkali metals or alkaline earth metals such as lithium,sodium, potassium, calcium, magnesium, and aluminum salts, and the like,and nontoxic quaternary ammonia and amine cations including ammonium,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, triethylamine, diethylamine, ethylamine and the such as.Other representative organic amines useful for the formation of baseaddition salts include ethylenediamine, ethanolamine, diethanolamine,piperidine, and piperazine.

The term “pharmaceutically acceptable ester”, as used herein, refers toesters of compounds of the invention which hydrolyze in vivo and includethose that break down readily in the human body to leave the parentcompound or a salt thereof. Examples of pharmaceutically acceptable,non-toxic esters of the invention include C₁-to-C₆ alkyl esters andC₅-to-C₇ cycloalkyl esters, although C₁-to-C₄ alkyl esters arepreferred. Esters of the compounds of formula (I) may be preparedaccording to conventional methods. For example, such esters may beappended onto hydroxy groups by reaction of the compound that containsthe hydroxy group with acid and an alkylcarboxylic acid such as aceticacid, or with acid and an arylcarboxylic acid such as benzoic acid. Inthe case of compounds containing carboxylic acid groups, thepharmaceutically acceptable esters are prepared from compoundscontaining the carboxylic acid groups by reaction of the compound withbase such as triethylamine and an alkyl halide, alkyl triflate, forexample with methyl iodide, benzyl iodide, cyclopentyl iodide. They alsomay be prepared by reaction of the compound having a carboxylic acidmoiety with an acid such as hydrochloric acid and an alcohol suchmethanol or ethanol.

The term “pharmaceutically acceptable amide”, as used herein, refers tonon-toxic amides of the invention derived from ammonia, primary C₁-to-C₆alkyl amines and secondary C₁-to-C₆ dialkyl amines. In the case ofsecondary amines, the amine may also be in the form of a 5- or6-membered heterocycle containing one nitrogen atom. Amides derived fromammonia, C₁-to-C₃ alkyl primary amides and C₁-to-C₂ dialkyl secondaryamides are preferred. Amides of the compounds of formula (I) may beprepared according to conventional methods. Pharmaceutically acceptableamides are prepared from compounds containing primary or secondary aminegroups by reaction of the compound that contains the amino group with analkyl anhydride, aryl anhydride, acyl halide, or aryl acid chloride. Inthe case of compounds containing carboxylic acid groups, thepharmaceutically acceptable amides are prepared from compoundscontaining the carboxylic acid groups by reaction of the compound withbase such as triethylamine, a dehydrating agent such as dicyclohexylcarbodiimide or carbonyl diimidazole, and an alkyl amine, dialkylamine,for example with methylamine, diethylamine, piperidine. The compositioncan contain a compound of the invention in the form of apharmaceutically acceptable prodrug.

The term “pharmaceutically acceptable prodrug” or “prodrug”, as usedherein, represents those prodrugs of the compounds of the inventionwhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, commensurate witha reasonable benefit/risk ratio, and effective for their intended use.Prodrugs of the invention may be rapidly transformed in vivo to a parentcompound of formula (I), for example, by hydrolysis in blood. A thoroughdiscussion is provided in T. Higuchi and V. Stella, Pro-drugs as NovelDelivery Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B.Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press (1987), herebyincorporated by reference.

The invention contemplates pharmaceutically active compounds eitherchemically synthesized or formed by in vivo biotransformation tocompounds of formula (I).

The compounds and processes of the invention will be better understoodby reference to the following examples, which are intended as anillustration of and not a limitation upon the scope of the invention.

Unless otherwise described, reactions were carried out under ambientconditions (ranging 17-27° C.), under nitrogen. Unless otherwisedescribed, column chromatography means flash chromatography carried outusing silica gel, a technique well known to those of ordinary skill inthe art of organic synthesis.

EXAMPLES Example 1(R)-4′-(3-(methylamino)pyrrolidin-1-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amineExample 1A spiro[4.5]decan-6-one

To a solution of bi(cyclopentane)-1,1′-diol (5.16 g, 29.4 mmol) inCH₂Cl₂ (80 mL), cooled to −20° C., was added trimethoxymethane (3.22 mL,29.4 mmol), followed by boron trifluoride etherate (2.98 mL, 23.52mmol). The cold bath was removed, and the reaction was stirred atambient temperature for 2 hours. The mixture was then diluted withCH₂Cl₂ (100 mL), washed with saturated NaHCO₃, dried with MgSO₄, andconcentrated under reduced pressure. The resulting residue waschromatographed on silica gel (100% hexane to 15:85 EtOAc/hexane,eluant) to provide the title compound. ¹H NMR (300 MHz, CDCl₃) δ 2.40(t, 2H), 2.00-2.11 (m, 2H), 1.78-1.87 (m, 2H), 1.71 (t, 4H), 1.59 (t,4H), 1.39 (t, 2H). MS (DCI⁺) m/z 153 (M+H).

Example 1B Methyl 6-oxospiro[4.5]decane-7-carboxylate

A solution of diisopropylamine (5.97 mL, 41.9 mmol) in ether (30 mL) wascooled to −78° C. and then was treated slowly with n-butyllithium (16.75mL, 41.9 mmol). The mixture was stirred at −78° C. for 30 minutes, thenthis solution was transferred via cannula into a −78° C. solution ofExample 1A (4.25 g, 27.9 mmol) in ether (30 mL). The mixture was stirredat this temperature for 30 minutes and then was treated with dimethylcarbonate (23.50 mL, 279 mmol). The resulting mixture was warmed toambient temperature and stirred for 16 hours. The mixture was quenchedwith saturated NH₄Cl and diluted with ether (100 mL), then the layerswere separated. The aqueous layer was extracted with additional ether,then the organic layers were combined, dried with MgSO₄, andconcentrated under reduced pressure. The residue was chromatographed onsilica gel (100% hexane to 85:15 EtOAc/hexanes, eluant) to provide thetitle product. ¹H NMR (300 MHz, CDCl₃) δ 12.40-12.42 (m, 1H), 3.72-3.76(m, 3H), 2.18-2.26 (m, 2H), 2.00-2.12 (m, 2H), 1.74-1.86 (m, 2H),1.57-1.62 (m, 2H), 1.54-1.57 (m, 2H), 1.35-1.48 (m, 4H). MS (DCI+) m/z211 (M+H).

Example 1C2′-amino-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-4′-ol

A solution of Example 1B (4.5 g, 21.4 mmol), guanidine hydrochloride(6.13 g, 64.2 mmol), and K₂CO₃ (9.46 g, 68.5 mmol) in DMF (30 mL) washeated at 105-110° C. for 3 hours. The mixture was then filtered througha layer of diatomaceous earth, and the filter pad was washed with asmall amount of DMF. Approximately two volumes of water were then added,and the pH of the resulting mixture was adjusted to pH 6-7 with HOAc.The precipitate was collected, washed with H₂O, and dried under vacuumto provide the title product. ¹H NMR (300 MHz, DMSO-d₆) δ 10.50-10.61(m, 1H), 5.98-6.08 (m, 2H), 2.20 (t, 2H), 1.95-2.04 (m, 2H), 1.68-1.76(m, 2H), 1.61-1.68 (m, 2H), 1.48-1.58 (m, 4H), 1.34-1.45 (m, 2H). MS(DCI⁺) m/z 220 (M+H).

Example 1D2′-amino-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazoline]-4′-yl4-methylbenzenesulfonate

A solution of Example 1C (2.91 g, 13.27 mmol), p-toluenesulfonylchloride (3.79 g, 19.91 mmol), and DMAP (324 mg, 2.65 mmol) in CH₂Cl₂(60 mL) was treated with TEA (3.7 ml, 4.40 mmol) at ambient temperature,and the resulting solution was stirred for 3 hours. It was then dilutedwith CH₂Cl₂ (100 mL) and H₂O (50 mL), and the layers were separated. Theorganic layer was dried with MgSO₄ and concentrated under reducedpressure, then the residue was chromatographed on silica gel (1:2:2EtOAc/CH₂Cl₂/hexane, eluant) to provide the title product (750 mg). ¹HNMR (300 MHz, CD₃OD) δ 7.95 (d, 2H), 7.44 (d, 2H), 2.45-2.47 (m, 3H),2.40-2.45 (m, 2H), 1.99-2.10 (m, 2H), 1.79-1.90 (m, 2H), 1.65-1.75 (m,6H), 1.52-1.62 (m, 2H). MS (DCI⁺) m/z 374 (M+H).

Example 1E (1-Benzyl-(3R)-pyrrolidin-3-yl)-methyl-carbamic Acidtert-butyl Ester

To a solution of (3R)-(−)-1-benzyl-3-(methylamino)pyrrolidine (200 mg,1.05 mmol) and di-tert-butyl-dicarbonate (230 mg, 1.06 mmol) in MeOH (10mL) was added NaOH (10%, 4 mL), and the mixture was stirred at ambienttemperature for 1 hour. The mixture was diluted with H₂O (20 mL) andEtOAc (100 mL). The organic layer was separated, and the aqueous layerwas extracted with additional EtOAc. The combined organic layers weredried with MgSO₄, filtered, and concentrated under reduced pressure toprovide the title compound. ¹H NMR (300 MHz, CD₃OD): δ 7.32 (m, 5H),4.71 (m, 1H), 2.81 (s, 3H), 2.73 (m, 1H), 2.60 (dd, J=27 Hz, J=15 Hz,2H), 2.53 (m, 2H), 2.07 (m, 1H), 1.80 (m, 1H), 1.43 (s, 9H). MS (DCI⁺)m/z 291 (M+H).

Example 1F (R)-Methyl-pyrrolidin-3-yl-carbamic Acid tert-butyl Ester

To a solution of Example 1E (285 mg, 0.98 mmol) in 4.4% HCO₂H/MeOH (20mL) under a nitrogen atmosphere was added Pd(OH)₂ on carbon (20%, 40mg), and the resulting mixture was heated at 60° C. for 16 hours. Themixture was cooled to room temperature and filtered through a layer ofdiatomaceous earth, the filter pad was washed with extra MeOH (30 mL),and the filtrate was concentrated under reduced pressure. The residuewas diluted with CH₂Cl₂ (30 mL) and washed with 1 M NaOH, then theorganic solution was dried (MgSO₄), filtered, and concentrated underreduced pressure to provide the title compound. ¹H NMR (300 MHz, CD₃OD)δ 4.57 (d, J=6 Hz, 1H), 3.03 (m, 2H), 2.87 (m, 1H), 2.79 (s, 3H), 2.76(m, 1H), 1.99 (m, 1H), 1.79 (m, 1H), 1.46 (s, 9H). MS (DCI⁺) m/z 201(M+H).

Example 1G (R)-tert-butyl1-(2′-amino-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazoline]-4′-yl)pyrrolidin-3-yl(methyl)carbamate

A microwave reaction vessel was charged with Example 1D (40 mg, 0.11mmol), Example 1F (45 mg, 0.16 mmol), acetonitrile (3 mL), andtriethylamine (0.1 mL), then the mixture was heated under microwaveirradiation at 150° C. for 10 minutes. The mixture was cooled to ambienttemperature and concentrated under reduced pressure, and the resultingresidue was chromatographed on silica gel (100% EtOAc to 95-5MeOH/EtOAc, eluant) to provide the title product.

Example 1H(R)-4′-(3-(methylamino)pyrrolidin-1-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine

A solution of Example 1G (38 mg, 0.09 mmol) in CH₂Cl₂ (2 mL) was treatedwith trifluoroacetic acid (0.1 mL) at ambient temperature, and thereaction was stirred for 16 hours. The mixture was diluted with CH₂Cl₂(20 mL) and washed with 1N NaOH and water. The organic layer was dried(MgSO₄) and concentrated under reduced pressure, and the resultingresidue was chromatographed on silica gel (0.8:7.2:92 NH₄OH/MeOH/CH₂Cl₂,eluant) to provide the title product. ¹H NMR (300 MHz, CD₃OD) δ3.55-3.78 (m, 3H), 3.37-3.44 (m, 1H), 3.22 (t, 1H), 2.57-2.65 (m, 2H),2.38-2.41 (m, 3H), 2.02-2.17 (m, 3H), 1.51-1.91 (m, 11H). MS (DCI⁺) m/z302 (M+H).

Example 24′-(piperazin-1-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine

A microwave reaction vessel was charged with Example 1D (35 mg, 0.094mmol), piperazine (26 mg, 0.28 mmol), triethylamine (0.02 mL, 0.14mmol), and acetonitrile (3 mL). The mixture was heated under microwaveirradiation at 150° C. for 10 minutes. The mixture was then cooled toambient temperature and concentrated under reduced pressure. Theresulting residue was chromatographed on silica gel (0.8:7.2:92NH₄OH/MeOH/CH₂Cl₂, eluant) to provide the title product. ¹H NMR (300MHz, CD₃OD) δ 3.22 (t, 4H), 2.90 (t, 4H), 2.47 (t, 2H), 2.03-2.14 (m,2H), 1.81-1.91 (m, 2H), 1.52-1.81 (m, 8H). MS (DCI⁺) m/z 288 (M+H).

Example 34′-(3-(methylamino)azetidin-1-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amineExample 3A 1-benzhydryl-N-methylazetidin-3-amine

A solution of 1-benzhydryl-azetidin-3-ol (15 g, 62.7 mmol) in pyridine(60 mL) was chilled to 0° C., then treated with methanesulfonyl chloride(6.3 mL, 81 mmol). The reaction was warmed to room temperature andstirred for 3 hours. The mixture was partitioned between ether (300 mL)and H₂O (150 mL), and the ether layer was washed with H₂O and brine,dried (MgSO₄), and concentrated to provide the crude methanesulfonate.This crude methanesulfonate was taken up in DMF (60 mL) and treated withmethyl amine (40% in H₂O, 90 mL), and the reaction was stirred at 85° C.for 48 hours. After cooling to room temperature, the mixture waspartitioned between H₂O (200 mL) and EtOAc (400 mL). The aqueous layerwas extracted with additional EtOAc, then the combined organics wereextracted with 2N HCl (2×200 mL). The acidic aqueous extracts werecombined, basified with 50% aqueous NaOH, and extracted with ether.Finally, these ethereal extracts were washed with brine, dried (MgSO₄),concentrated under reduced pressure, and purified by chromatography onsilica gel (0.4:3.6:96 NH₄OH/MeOH/CH₂Cl₂, eluant) to afford the titlecompound. ¹H NMR (300 MHz, CDCl₃): δ 7.36-7.4 (m, 4H), 7.24-7.29 (m,4H), 7.15-7.20 (m, 2H), 3.46 (t, J=6 Hz, 2H), 3.33 (m, 1H), 2.83 (t, J=6Hz, 2H), 2.26 (s, 3H). MS (DCI⁺) m/z 254 (M+H).

Example 3B tert-butyl azetidin-3-yl(methyl)carbamate

The title compound was prepared using the procedures of Examples 1E and1F, substituting the product from Example 3A for(3R)-(−)-1-benzyl-3-(methylamino)pyrrolidine. ¹H NMR (300 MHz, CDCl₃): δ3.77 (t, J=6 Hz, 2H), 3.62 (t, J=6 Hz, 2H), 3.55 (m, 1H), 2.87 (s, 3H),1.45 (s, 9H). MS (DCI⁺) m/z 187 (M+H).

Example 3C4′-(3-(methylamino)azetidin-1-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine

The title compound was prepared using the procedures outlined inExamples 1G and 1H, substituting the product from Example 3B for theproduct from Example 1F. ¹H NMR (300 MHz, CD₃OD) δ 4.35 (t, 2H), 4.34(t, 2H), 3.50-3.60 (m, 1H), 2.46 (t, 2H), 2.32-2.34 (m, 3H), 1.99-2.10(m, 2H), 1.51-1.89 (m, 10H). MS (DCI⁺) m/z 288 (M+H).

Example 4(R)-4′-(3-aminopyrrolidin-1-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine

The title compound was prepared using the procedures outlined inExamples 1G and 1H, substituting (R)-tert-butyl pyrrolidin-3-ylcarbamatefor the product from Example 1F. ¹H NMR (300 MHz, CDCl₃) δ 4.36-4.45 (m,2H), 3.67-3.78 (m, 2H), 3.51-3.64 (m, 2H), 3.27 (dd, 1H), 2.53-2.60 (m,2H), 2.03-2.17 (m, 3H), 1.78-1.91 (m, 2H), 1.45-1.74 (m, 9H). MS (DCI⁺)m/z 288 (M+H).

Example 5(S)-4′-(3-aminopyrrolidin-1-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine

The title compound was prepared using the procedures outlined inExamples 1G and 1H, substituting (S)-tert-butyl pyrrolidin-3-ylcarbamatefor the product from Example 1F. ¹H NMR (300 MHz, CD₃OD) δ 3.87-4.16 (m,5H), 2.69-2.76 (m, 2H), 2.33-2.47 (m, 1H), 2.09-2.22 (m, 1H), 1.64-1.97(m, 12H). MS (DCI⁺) m/z 288 (M+H).

Example 64′-((3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amineExample 6A (3aR,6aR)-Hexahydro-pyrrolo[3,4-b]pyrrole-1,5-dicarboxylicAcid 5-benzyl Ester 1-tert-butyl Ester

(3aR,6aR)-Hexahydro-pyrrolo[3,4-b]pyrrole-1-carboxylic acid tert-butylester (3.0 g, 12.5 mmol) and N-(benzyloxycarbonyloxy)-succinimide (3.42g, 13.7 mmol) were mixed in 15 mL of dichloromethane. The mixture wasstirred at room temperature overnight and then concentrated under vacuumto provide the crude product. The residue was purified by chromatographyon silica gel (4:1 hexane-EtOAc, eluant) to provide the title compound.¹H NMR (CDCl3) δ 7.29-7.43 (m, 5H), 5.13 (s, 2H), 4.15-4.33 (m, 1H),3.39-3.74 (m, 5H), 3.20-3.37 (m, 1H), 2.84-2.96 (m, 1H), 1.92-2.03 (m,1H), 1.66-1.82 (m, 1H), 1.46 (s, 9H). MS: (DCI⁺) m/z 347 (M+H).

The starting material(3aR,6aR)-hexahydro-pyrrolo[3,4-b]pyrrole-1-carboxylic acid tert-butylester (CAS # 370880-09-4) may be prepared as described in theliterature, for example the method of Schenke, et al., “Preparation of2,7-Diazabicyclo[3.3.0]octanes” U.S. Pat. No. 5,071,999 (1991) whichprovides a racemate which may be resolved by chromatography on a chiralcolumn or by fractional crystallization of diastereomeric salts, or asdescribed in Basha, et al. “Substituted diazabicycloalkane derivatives”,US 2005101602 (2005).

Example 6B4′-((3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine

The Boc group of Example 6A was removed as outlined in the procedure forExample 1H, substituting Example 6A for Example 1G. The resulting(3aR,6aR)-benzyl hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate wasreacted with the product from Example 1D according to the procedure ofExample 1G, substituting (3aR,6aR)-benzylhexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate for Example 1F. Theproduct from this reaction (520 mg) was then heated at 50° C. under a H₂atmosphere (60 psi) in the presence of 20% Pd(OH)₂ on charcoal. Aftercooling to room temperature, the hydrogen atmosphere was displaced withnitrogen, and the mixture was filtered through a layer of diatomaceousearth and concentrated under reduced pressure to provide the titlecompound. ¹H NMR (300 MHz, CD₃OD) δ 4.70-4.77 (m, 1H), 3.74-3.85 (m,1H), 3.50-3.59 (m, 1H), 2.99-3.14 (m, 2H), 2.72-2.89 (m, 3H), 2.52-2.59(m, 2H), 2.16-2.28 (m, 1H), 2.01-2.11 (m, 1H), 1.63-1.97 (m, 9H),1.42-1.54 (m, 3H). MS (DCI⁺) m/z 314 (M+H).

Example 74′-((3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine

The title compound was prepared using the procedures outlined inExamples 1G and 1H, substituting (3aS,6aS)-tert-butylhexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (CAS#: 370882-55-6,prepared according to the procedures in the patent US 2005101602) forthe product from Example 1F. ¹H NMR (300 MHz, CD₃OD) δ 4.73-4.80 (m,1H), 3.78-3.88 (m, 1H), 3.52-3.61 (m, 1H), 3.07-3.20 (m, 2H), 2.78-2.93(m, 3H), 2.54-2.61 (m, 2H), 2.15-2.27 (m, 1H), 2.02-2.13 (m, 1H),1.63-1.96 (m, 9H), 1.44-1.54 (m, 3H). MS (DCI⁺) m/z 314 (M+H).

Example 84′-(1,4-diazepan-1-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine

The title compound was prepared using the procedures outlined n Example2, substituting homopiperazine for piperazine. ¹H NMR (300 MHz, CDCl₃) δ4.47-4.53 (m, 2H), 3.58 (t, 4H), 3.02 (t, 2H), 2.91 (t, 2H), 2.42-2.48(m, 2H), 2.06-2.17 (m, 2H), 1.79-1.90 (m, 4H) 1.63-1.72 (m, 6H)1.48-1.56 (m, 2H). MS (DCI⁺) m/z 302 (M+H).

Example 94′-((4aR,7aR)-tetrahydro-1H-pyrrolo[3,4-b]pyridin-6(2H,7H,7aH)-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine

The title compound was prepared using the procedures outlined inExamples 1G and 1H, substituting tert-butyloctahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate (CAS# 159877-36-8) forthe product from Example 1D. ¹H NMR (300 MHz, CDCl₃) δ 4.38-4.47 (m,2H), 3.70-3.82 (m, 2H), 3.38-3.52 (m, 2H), 3.31 (td, 1H), 3.00 (dt, 1H),2.57-2.69 (m, 3H), 2.16-2.26 (m, 2H), 1.96-2.07 (m, 1H), 1.79-1.92 (m,2H), 1.64-1.76 (m, 6H), 1.42-1.59 (m, 6H). MS (DCI⁺) m/z 328 (M+H).

Example 10N4′-(1-methylpiperidin-4-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazoline]-2′,4′-diamine

The title compound was prepared using the procedures outlined in Example2, substituting 1-methylpiperidin-4-amine for piperazine. ¹H NMR (300MHz, CDCl₃) δ 4.39-4.46 (m, 2H), 4.14-4.21 (m, 1H), 3.90-4.03 (m, 1H),2.72-2.82 (m, 2H), 2.28-2.30 (m, 3H), 2.19 (t, 2H), 1.99-2.15 (m, 5H),1.81-1.90 (m, 2H) 1.72-1.79 (m, 2H), 1.64-1.71 (m, 2H), 1.59-1.63 (m,2H), 1.43-1.54 (m, 4H). MS (DCI⁺) m/z 316 (M+H).

Example 11 Methyl4-amino-1-(2′-amino-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazoline]-4′-yl)piperidine-4-carboxylate

The title product was prepared using the procedures outlined in Examples1G and 1H, substituting methyl4-(tert-butoxycarbonylamino)piperidine-4-carboxylate (CAS# 115655-44-2)for the product from Example 1D. ¹H NMR (300 MHz, CDCl₃) δ 4.50 (s, 2H),3.74 (s, 3H), 3.30-3.36 (m, 4H), 2.45 (t, J=4.58 Hz, 2H), 2.04-2.21 (m,4H), 1.79-1.92 (m, J=4.07 Hz, 2H), 1.49-1.73 (m, 10H). MS (DCI⁺) m/z 360(M+H).

Example 124-amino-1-(2′-amino-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazoline]-4′-yl)piperidine-4-carboxylicAcid

A solution of the product from Example 11 (30 mg, 0.083 mmol) in MeOH (5mL) was treated with NaOH solution (1 mL, 10%) and stirred for 16 hours.The mixture was concentrated under reduced pressure, and the resultingoil was chromatographed on silica gel (6:1:1 EtOAc/HCO₂H/H₂O, eluant).The fractions containing the still-impure product were combined andconcentrated under reduced pressure, then the residue was againchromatographed on silica gel, this time eluting with NH₄OH/MeOH/CH₂Cl₂(1.5:13.5:85), to provide the title product. ¹H NMR (300 MHz, CD₃OD) δ3.70-3.81 (m, 2H), 3.45-3.57 (m, 2H), 2.52 (t, J=5.43 Hz, 2H), 2.25-2.36(m, 2H), 1.98-2.09 (m, 2H), 1.76-1.94 (m, 6H), 1.61-1.74 (m, 6H). MS(DCI⁺) m/z 346 (M+H) and 368 (M+Na).

Example 134′-(3-aminoazetidin-1-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine

The title compound was prepared according to the procedures of Examples1G and 1H, substituting tert-butyl azetidin-3-ylcarbamate for theproduct from Example 1D. ¹H NMR (300 MHz, CDCl₃) δ 4.49 (br, 2H), 3.33(m, 4H), 2.38-2.52 (m, 3H), 2.02-2.22 (m, 4H), 1.79-1.93 (m, 2H),1.53-1.68 (m, 6H). MS (DCI⁺) m/z 274 (M+H).

Example 144′-(2-(dimethylamino)ethoxy)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amineExample 14A4′-chloro-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine

To a solution of the product from Example 1D (300 mg, 0.803 mmol) inCH₂Cl₂ (10 mL) was added HCl in dioxane (0.6 mL, 4M), and the mixturestirred at ambient temperature for 16 hours. The mixture wasconcentrated under reduced pressure, and the resulting residue waschromatographed on silica gel, eluting with 5-20% EtOAc/hexane, toprovide the title product. ¹H NMR (300 MHz, CDCl₃) δ 4.79 (s, 2H), 2.60(t, J=6.35 Hz, 2H), 2.02-2.13 (m, 2H), 1.82-1.92 (m, 2H), 1.63-1.79 (m,6H), 1.55-1.62 (m, 2H). MS (DCI⁺) m/z 357 (M+H).

Example 14B4′-(2-(dimethylamino)ethoxy)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine

A solution of 2-(dimethylamino)ethanol (63.9 μL, 0.631 mmol) in THF (5mL) was treated with potassium tert-butoxide (78 mg, 0.694 mmol) at 0°C., and the reaction mixture was stirred for 30 minutes at ambienttemperature. It was then treated with a solution of the product fromExample 14A (30 mg, 0.126 mmol) in THF (2 mL) at ambient temperature,and the whole was stirred for 2 hours. The mixture was diluted withCH₂Cl₂ (20 mL) and H₂O (10 mL), then the organic layer was separated,dried with MgSO₄, and concentrated under reduced pressure. The resultingresidue was chromatographed on silica gel, eluting withNH₄OH/MeOH/CH₂Cl₂ (0.8/7.2/92), to afford the title product. ¹H NMR (300MHz, CDCl₃) δ 4.56 (s, 2H), 4.37 (t, 2H), 2.68 (t, J=5.93 Hz, 2H), 2.43(t, J=6.10 Hz, 2H), 2.32 (s, 6H), 2.01-2.13 (m, 2H), 1.79-1.90 (m, 2H),1.59-1.74 (m, 6H), 1.47-1.57 (m, 2H). MS (DCI⁺) m/z 291 (M+H).

Example 15(R)-4′-(1-methylpyrrolidin-3-yloxy)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine

The title product was prepared using the procedures outlined in Example14B, substituting (R)-1-methylpyrrolidin-3-ol for2-(dimethylamino)ethanol. ¹H NMR (300 MHz, CDCl₃) δ 4.54 (s, 2H), 2.87(dd, J=10.85, 6.44 Hz, 1H), 2.73-2.80 (m, 1H), 2.65-2.72 (m, 1H),2.39-2.48 (m, 3H), 2.37 (s, 3H), 2.24-2.35 (m, J=6.10 Hz, 1H), 2.02-2.12(m, 2H), 1.90-2.00 (m, 1H), 1.78-1.90 (m, 3H), 1.59-1.73 (m, 6H),1.47-1.57 (m, 2H). MS (DCI⁺) m/z 303 (M+H).

Example 164-(piperazin-1-yl)-5,6,7,8-tetrahydrospiro[cyclohepta[d]pyrimidine-9,1′-cyclohexan]-2-amineExample 16A spiro[5.6]dodecan-7-one

To a solution of cycloheptanone (2.1 mL, 17.83 mmol) and potassiumtert-butoxide (2.60 g, 23.18 mmol) in THF (10 mL) was dropwise added asolution of 1-chloro-5-iodopentane (2.74 mL, 19.61 mmol) in THF (10 mL).The mixture was stirred at ambient temperature for 16 hours. It was thendiluted with ether (200 mL), washed with saturated NH₄Cl and brine,dried with MgSO₄, and concentrated under reduced pressure. The resultingresidue was chromatographed on silica gel (95:5 hexane-EtOAc, eluant) toprovide the title compound. ¹H NMR (300 MHz, CDCl₃) δ 2.50 (t, 2H),1.55-1.79 (m, 8H), 1.30-1.52 (m, 10H). MS (DCI⁺) m/z 198 (M+H).

Example 16B Methyl 7-oxospiro[5.6]dodecane-8-carboxylate

A solution of diisopropylamine (1.130 mL, 7.93 mmol) in THF (10 mL) wastreated with n-butyllithium (3.17 mL, 7.93 mmol) at −78° C., and thereaction was stirred at this temperature for 30 minutes. The abovesolution was then transferred via cannula into a solution of the productfrom Example 16A (1.1 g, 6.10 mmol) in THF (10 mL) at −78° C., and theresulting mixture was stirred at this temperature for 30 minutes.Dimethyl carbonate (5.14 mL, 61.0 mmol) was added, the cold bath wasremoved, and HMPA (1.062 mL, 6.10 mmol) was then added. The resultingmixture was stirred at ambient temperature for 16 hours. It was quenchedwith HCl (1N) and diluted with ether (200 mL), then the organic layerwas separated, washed with H₂O and brine, dried with MgSO₄, andconcentrated under reduced pressure. The residue was chromatographed onsilica gel (95:5 hexane-EtOAc, eluant) to provide the title compound. ¹HNMR (300 MHz, CDCl₃) δ 3.88 (dd, J=11.87, 3.05 Hz, 1H), 3.68 (s, 3H),2.06-2.16 (m, 1H), 1.92-2.04 (m, 2H), 1.59-1.90 (m, 5H), 1.29-1.51 (m,8H), 0.98-1.16 (m, 2H). MS (DCI⁺) m/z 239 (M+H).

Example 16C2-amino-5,6,7,8-tetrahydrospiro[cyclohepta[d]pyrimidine-9,1′-cyclohexan]-4-ol

A mixture of guanidine hydrochloride (430 mg, 4.5 mmol), the productfrom Example 16B (430 mg, 1.8 mmol), and potassium carbonate (623 mg,4.5 mmol) in DMF (8 mL) was heated at 100° C. for 16 hours. Then, thetemperature was raised to 120° C. for 2 hours. The mixture was cooled toambient temperature and filtered through a layer of diatomaceous earth,then the filter pad was washed with a small amount of DMF. The filtratewas concentrated under reduced pressure, and the residue waschromatographed on silica gel (10:45:45 MeOH/CH₂Cl₂/EtOAc, eluant) toprovide the title compound as a white solid. ¹H NMR (300 MHz, DMSO-d₆)ppm 10.62 (s, 1H), 6.04 (s, 2H), 2.57-2.64 (m, 2H), 1.93-2.05 (m, 2H),1.60-1.71 (m, 4H), 1.35-1.57 (m, 9H), 1.15-1.28 (m, 1H). MS (DCI⁺) m/z248 (M+H).

Example 16D2-amino-5,6,7,8-tetrahydrospiro[cyclohepta[d]pyrimidine-9,1′-cyclohexane]-4-yl4-methylbenzenesulfonate

The title compound was prepared using the procedures outlined in Example1D, substituting the product from Example 16C for the product fromExample 1C. ¹H NMR (300 MHz, CDCl₃) δ 7.93 (d, J=8.48 Hz, 2H), 7.34 (d,J=8.14 Hz, 1H), 4.69 (s, 2H), 2.70-2.77 (m, 2H), 2.46 (s, 3H), 1.89-2.02(m, 2H), 1.65-1.75 (m, 4H), 1.41-1.64 (m, 10H), 1.23-1.34 (m, 1H). MS(DCI⁺) m/z 402 (M+H).

Example 16E A-1047450.04-(piperazin-1-yl)-5,6,7,8-tetrahydrospiro[cyclohepta[d]pyrimidine-9,1′-cyclohexan]-2-amine

The title compound was prepared using the procedures outlined in Example2, substituting the product from Example 16D for the product fromExample 1D. ¹H NMR (300 MHz, CDCl₃) δ 4.52 (s, 2H), 3.07-3.15 (m, 4H),2.93-2.98 (m, 4H), 2.63-2.70 (m, 2H), 2.01-2.16 (m, 2H), 1.42-1.80 (m,14H). MS (DCI⁺) m/z 316 (M+H).

Example 17(R)-4-(3-aminopyrrolidin-1-yl)-5,6,7,8-tetrahydrospiro[cyclohepta[d]pyrimidine-9,1′-cyclohexan]-2-amine

(R)-tert-butyl pyrrolidin-3-ylcarbamate (56 mg, 0.3 mmol), the productfrom Example 16D (60 mg, 0.15 mmol), and triethylamine (0.042 mL, 0.3mmol) were placed in a 10 mL vial. The vial was capped, and the mixturewas heated at 70° C. for 16 hours. It was then cooled to ambienttemperature and concentrated under reduced pressure. The residue waschromatographed on silica gel, eluting with 97:3 EtOAc-MeOH, to providethe Boc-protected intermediate (35 mg). The intermediate was dissolvedin CH₂Cl₂ (2 mL) and stirred with trifluoroacetic acid (0.1 mL) for 16hours, then the mixture was basified with NaOH (10%) and diluted withCH₂Cl₂ (20 mL). The organic layer was separated, dried with MgSO₄, andconcentrated under reduced pressure. The residue was chromatographed onsilica gel (0.8:7.2:92 NH₄OH/MeOH/CH₂Cl₂, eluant) to afford the titlecompound. ¹H NMR (300 MHz, CDCl₃) δ 4.51 (s, 2H), 3.53-3.65 (m, 3H),3.42-3.52 (m, 1H), 3.16 (dd, J=10.11, 4.56 Hz, 1H), 2.57 (dd, J=6.74,4.36 Hz, 2H), 2.00-2.19 (m, 3H), 1.36-1.85 (m, 15H). MS (DCI⁺) m/z 316(M+H).

Example 184-((4aR,7aR)-tetrahydro-1H-pyrrolo[3,4-b]pyridin-6(2H,7H,7aH)-yl)-5,6,7,8-tetrahydrospiro[cyclohepta[d]pyrimidine-9,1′-cyclohexan]-2-amine

The title compound was prepared using the procedures outlined in Example17, substituting cis-tert-butyloctahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate (CAS# 159877-36-8) for(R)-tert-butyl pyrrolidin-3-ylcarbamate. ¹H NMR (300 MHz, CDCl₃) δ 4.40(s, 2H), 3.71-3.83 (m, 2H), 3.30 (t, J=4.36 Hz, 2H), 3.14-3.26 (m, 2H),2.98-3.06 (m, 1H), 2.55-2.68 (m, 3H), 2.13-2.26 (m, 2H), 1.97-2.09 (m,1H), 1.66-1.82 (m, 8H), 1.30-1.64 (m, 9H). MS (DCI⁺) m/z 356 (M+H).

Example 194-(piperazin-1-yl)-1′,3′,5,6,7,8-hexahydrospiro[cyclohepta[d]pyrimidine-9,2′-inden]-2-amineExample 19A 1′,3′-dihydrospiro[cycloheptane-1,2′-inden]-2-one

A solution of cycloheptanone (5.30 mL, 45.0 mmol) and1,2-bis(bromomethyl)benzene (11.88 g, 45.0 mmol) in toluene (65 mL) wastreated all at once with potassium tert-butoxide (10.10 g, 90 mmol). Thereaction stirred for 20 hours at 85° C. After this time, the mixture waswashed with 25 mL water and 65 mL of 15% HCl, then the aqueous washeswere extracted three times with ether. The combined organics were washedwith brine, dried over Na₂SO₄, and evaporated to a yellow oil, which waspurified by chromatography on silica gel (93:7 to 85:15 EtOAc-hexane,eluant) to afford the title compound. ¹H NMR (300 MHz, d₆-DMSO) δ7.09-7.18 (m, 4H), 3.26 (d, J=16.0 Hz, 2H), 2.75 (d, J=16.0, 2H), 2.59(m, 2H), 1.84 (m, 2H), 1.57-1.66 (m, 4H), 1.47 (m, 2H). MS (DCI⁺) m/z215 (M+H, 232 (M+NH₄).

Example 19B Methyl2-oxo-1′,3′-dihydrospiro[cycloheptane-1,2′-indene]-3-carboxylate

A mixture of Example 19A (1.8 g, 8.40 mmol) in dimethyl carbonate (7.1mL, 84 mmol) was treated with sodium hydride (60% dispersion in mineraloil, 0.672 g, 16.80 mmol) and a catalytic amount of MeOH (2 drops), thenthe mixture was heated at reflux. After 3 hours, the reaction was cooledto room temperature, and then it was quenched with 2N HCl. The mixturewas extracted with ether, then the extracts were dried (Na₂SO₄) andevaporated. Purification by silica gel chromatography (10 to 25%EtOAc-hexane, eluant) afforded the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ 7.10-7.21 (m, 4H), 4.25 (dd, J=11.1, 2.8 Hz, 1H), 3.57 (s,3H), 3.51 (d, J=15.9 Hz, 1H), 3.15 (d, J=15.9 Hz, 1H), 3.00 (m, 1H),2.60 (d, J=16.3 Hz, 1H), 2.09 (m, 1H), 1.90 (d, J=5.2 Hz, 2H), 1.72-1.85(m, 2H), 1.44-1.56 (m, 2H), 1.02-1.15 (m, 1H). MS (DCI⁺) m/z 273 (M+H),290 (M+NH₄).

Example 19C2-amino-1′,3′,5,6,7,8-hexahydrospiro[cyclohepta[d]pyrimidine-9,2′-inden]-4-ol

A mixture of Example 19B (490 mg, 1.799 mmol), guanidine nitrate (439mg, 3.60 mmol), and potassium carbonate (497 mg, 3.60 mmol) in DMF (4mL) was heated overnight at 120° C. After this time, the mixture wascooled to room temperature, then poured into 50 mL of water. The pH wasadjusted to about 5 with acetic acid, then the precipitate was collectedby filtration, washed with water, and air-dried. The sample was furtherdried azeotropically with toluene to yield the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ 10.70 (br, 1H), 7.07-7.20 (m, 4H), 6.14 (br s, 2H),3.58 (d, J=16.0 Hz, 2H), 2.95 (m, 1H), 2.90 (m, 1H), 2.57-2.66 (m, 2H),1.59-1.74 (m, 4H), 1.49 (m, 2H). MS (DCI⁺) m/z 282 (M+H).

Example 19D2-amino-1′,3′,5,6,7,8-hexahydrospiro[cyclohepta[d]pyrimidine-9,2′-indene]-4-yl4-methylbenzenesulfonate

Example 19C (0.395 g, 1.404 mmol), p-toluenesulfonyl chloride (0.535 g,2.81 mmol), triethylamine (0.59 ml, 4.23 mmol), and DMAP (0.043 g, 0.351mmol) were stirred in dichloromethane (23 ml) overnight at roomtemperature. The mixture was then diluted with CH₂Cl₂ and washed withwater. The organics were dried over Na₂SO₄ and evaporated, thentriturated with EtOAc to yield an orange-brown solution and a black tar.The solution was chromatographed on silica gel (15% EtOAc-hexane to 100%EtOAc, eluant) to yield the title compound. NMR (300 MHz, DMSO-d₆) δ7.98 (d, J=8.3 Hz, 2H), 7.48 (d, J=7.9 Hz, 2H), 7.08-7.22 (m, 4H), 6.64(br s, 2H), 3.56 (d, J=15.9 Hz, 2H), 3.04 (d, J=16.3 Hz, 2H), 2.61 (m,2H), 2.43 (s, 3H), 1.75 (m, 2H), 1.57-1.70 (m, 2H), 1.47 (m, 2H). MS(DCI⁺) m/z 436 (M+H).

Example 19E4-(piperazin-1-yl)-1′,3′,5,6,7,8-hexahydrospiro[cyclohepta[d]pyrimidine-9,2′-inden]-2-amine

Example 19D (0.191 g, 0.439 mmol), piperazine (0.050 g, 0.580 mmol), andtriethylamine (0.13 mL, 0.933 mmol) were heated in 2-methoxyethanol (2.5mL) at 115° C. overnight, then the mixture was evaporated in vacuo.Chromatography on silica gel (5 to 20% MeOH—CH₂Cl₂, eluant) afforded thep-toluenesulfonate salt of the title compound. ¹H NMR (300 MHz, DMSO-d₆)δ 7.47 (d, J=7.93 Hz, 2H), 7.08-7.20 (m, 6H), 5.99 (br s, 2H), 3.59 (m,2H), 2.96-3.18 (m, 11H), 2.62 (m, 2H), 2.29 (s, 3H), 1.65-1.80 (m, 4H),1.50-1.62 (m, 2H). MS (ESI⁺) 350 (M+H).

Example 20(R)-4-(3-aminopyrrolidin-1-yl)-1′,3′,5,6,7,8-hexahydrospiro[cyclohepta[d]pyrimidine-9,2′-inden]-2-amineExample 20A (R)-tert-butyl1-(2-amino-1′,3′,5,6,7,8-hexahydrospiro[cyclohepta[d]pyrimidine-9,2′-indene]-4-yl)pyrrolidin-3-ylcarbamate

The title compound was prepared according to the procedure of Example19E, substituting (R)-tert-butyl pyrrolidin-3-ylcarbamate forpiperazine. ¹H NMR (300 MHz, DMSO-d₆) δ 7.08-7.18 (m, 4H), 6.10 (br,2H), 5.65 (br s, 1H), 3.99 (m, 1H), 3.39-3.73 (m, 3H), 3.17-3.28 (m,3H), 2.95 (m, 3H), 2.58 (m, 2H), 2.28 (m, 1H), 1.64-1.79 (m, 4H), 1.57(m, 2H), 1.39 (s, 9H). MS (ESI⁺) m/z 450 (M+H).

Example 20B(R)-4-(3-aminopyrrolidin-1-yl)-1′,3′,5,6,7,8-hexahydrospiro[cyclohepta[d]pyrimidine-9,2′-inden]-2-amine

A solution of Example 20A (0.141 g, 0.314 mmol) in THF (10 mL) wastreated with hydrogen chloride (4M in dioxane, 3.2 mL, 12.80 mmol), andthe mixture was stirred for 2 hours at 60° C. The mixture was thenevaporated, and the residue was triturated with EtOAc. The precipitatewas collected by filtration and air-dried, then it was triturated againwith CH₂Cl₂ to afford the dihydrochloride salt of the title compound. ¹HNMR (300 MHz, DMSO-d₆) 8.22 (br, 2H), 7.21-7.27 (m, 4H), 3.88 (m, 2H),3.47-3.80 (m, 3H), 2.86-3.22 (m, 3H), 2.58-2.85 (m, 2H), 1.96-2.37 (m,3H), 1.91 (m, 1H), 1.46-1.85 (m, 5H). MS (ESI⁺) m/z 350 (M+H).

Determination of Biological Activity

There are many methods available to show the effectiveness of compoundsas histamine H₄ receptor ligands. Histamine H₄ receptors from mammalianspecies have been cloned. Methods to clone, express, and assess thepotency and functional activity of such cloned genes are well known tothose skilled in the art of molecular biology. Examples of methods ofcloning and expressing histamine H₄ receptors, and of assessing thepotency and functional activity, are described in Nguyen, et al.Molecular Pharmacology (2001) vol. 59 pp. 427-433; Zhu, et al. MolecularPharmacology (2001) vol. 59 pp. 434-441; Coge, et al., Biochemical andBiophysical Research Communications (2001) vol. 284, pp. 301-309; Liu,et al. Molecular Pharmacology (2001) vol. 59 pp. 420-426; Liu, et al.Journal of Pharmacology and Experimental Therapeutics (2001) v. 299, pp.121-130; and Thurmond, et al. Journal of Pharmacology and ExperimentalTherapeutics (2004) v. 309, pp. 404-413. In the present case, todetermine the potency and effectiveness of representative compounds ofthis invention as histamine-H₄ receptor ligands (H₄ receptor ligands),the following tests were conducted according to previously describedmethods (see Esbenshade, et al., Biochemical Pharmacology (2004), vol.68, pp. 933-945, and in Krueger, et al., Journal of Pharmacology andExperimental Therapeutics (2005) v. 314, pp. 271-281): histamine H₄receptors were cloned and stably expressed in HEK-293 (human embryonickidney) cells coexpressing a Gαqi5. Before testing, cells are loadedwith a Ca⁺² sensitive fluorescent dye, in this case Fluo-4. In the caseof partial agonist or agonist ligands, addition of compound to the cellsleads to the increase in intracellular Ca⁺², which is detected by FLIPR(Fluorescence Imaging Plate Reader; Molecular Devices, Sunnyvale,Calif.) technology. In a similar manner, compounds that are antagonistsor inverse agonists block the increase in fluorescence induced by thefull histamine H₄ agonist histamine, and partial agonists reduce theamount of fluorescence induced by the full histamine H₄ agonisthistamine. The fluorescence intensities measured before addition of thetest compound are subtracted from the fluorescence intensities at latertime points. Peak response values determined at each concentration ofligand are expressed as a percentage of the response obtained with thefull agonist histamine. Concentration versus response data are analyzedto obtain compound potency as Kb values for antagonists and inverseagonists and as EC₅₀ values for partial agonists.

TABLE 2 In vitro histamine H₄ potency of compounds in FLIPR Example #Potency (nM)  1 2.9  2 2.8  3 4.6  4 2.7  5 53  6 1097  7 1027  8 9.8  98.5 10 22 11 12624 12 21251 13 68851 14 7.8 15 20 16 48 17 47 18 99 1926915 20 499

Generally, representative compounds of the invention demonstratedpotencies in the above FLIPR assay from about 1 nM to about 70000 nM.Preferred compounds of the invention have potencies at histamine-H₄receptors from about 1 nM to about 100 nM. More preferred compounds ofthe invention have potencies at histamine H₄ receptors from about 1 nMto about 20 nM.

The potency of compounds of the invention in displacing ³H-histamine incompetition binding assays is assessed by methods described inEsbenshade, et al., Biochemical Pharmacology (2004), vol. 68, pp.933-945. In this assay, membranes were prepared from HEK-293 cellstransiently transfected with the pCINeo expression vector harboring thehistamine H₄ receptor by homogenization of the cells on ice in TE buffer(50 mM Tris-HCl buffer, pH 7.4, containing 5 mM EDTA), 1 mM benzamidine,2 μg/ml aprotinin, 1 g/ml leupeptin, and 1 μg/ml pepstatin. Thehomogenate was centrifuged at 40,000 g for 20 minutes at 4° C. This stepwas repeated, and the resulting pellet was resuspended in TE buffer.Aliquots were frozen at −70° C. until needed. On the day of assay,membranes were thawed and diluted with TE buffer. Competitionradioligand binding assays were performed with increasing concentrationsof test compound in the presence of [³H]-histamine incubated at 25° C.for 1 hour in a total volume of 0.5 mL of 50 mM Tris, 5 mM EDTA, pH 7.4.All binding reactions were terminated by filtration under vacuum ontopolyethylenimine (0.3%) presoaked Unifilters (PerkinElmer Life Sciences)or Whatman GF/B filters (Whatman, Clifton, N.J.), followed by threebrief washes with 4 ml of ice-cold TE buffer. Bound radiolabel wasdetermined by liquid scintillation counting. For all of the radioligandcompetition binding assays, IC₅₀ values and Hill slopes were determinedby Hill transformation of the data, and K_(i) values were determined bythe Cheng-Prusoff equation. The following table of representativehistamine H₄ receptor ligands is provided, along with potency values:

Compound Name (Example Number) Potency (nM)(R)-4′-(3-(methylamino)pyrrolidin-1-yl)- 2.66′,7′-dihydro-5′H-spiro[cyclopentane- 1,8′-quinazolin]-2′-amine (1)4′-(piperazin-1-yl)-6′,7′-dihydro-5′H- 1.1spiro[cyclopentane-1,8′-quinazolin]-2′- amine (2)4′-(3-(methylamino)azetidin-1-yl)-6′,7′- 1.4dihydro-5′H-spiro[cyclopentane-1,8′- quinazolin]-2′-amine (3)(R)-4′-(3-aminopyrrolidin-1-yl)-6′,7′- 4.6dihydro-5′H-spiro[cyclopentane-1,8′- quinazolin]-2′-amine (4)4′-(1,4-diazepan-1-yl)-6′,7′-dihydro-5′H- 2.8spiro[cyclopentane-1,8′-quinazolin]-2′- amine (8)4′-((4aR,7aR)-tetrahydro-1H- 3.4 pyrrolo[3,4-b]pyridin-6(2H,7H,7aH)-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane- 1,8′-quinazolin]-2′-amine (9)4-(piperazin-1-yl)-5,6,7,8- 9.3 tetrahydrospiro[cyclohepta[d]pyrimidine-9,1′-cyclohexan]-2-amine (16) (R)-4-(3-aminopyrrolidin-1-yl)-5,6,7,8- 18tetrahydrospiro[cyclohepta[d]pyrimidine- 9,1′-cyclohexan]-2-amine (17)

Generally, representative compounds of the invention demonstratepotencies from about 0.5 nM to about 20 nM. Preferred compounds of theinvention have potencies at histamine-H₄ receptors from about 0.5 nM toabout 10 nM. More preferred compounds of the invention have potencies athistamine H₄ receptors from about 0.5 nM to about 3 nM.

In addition to the utility of in vitro methods for characterizing thepotency of compounds at the H₄ receptor, there are animal disease modelsavailable that demonstrate the utility of compounds. There are a numberof methods to test the activity of compounds in different pain modelsthat are well known to those skilled in the art. A description of theformalin test in rats, of neuropathic pain models in rats, and generaldescriptions of methods of testing and descriptions of pain models arefound in the book ‘Drug Discovery and Evaluation, 2^(nd) edition’ (H.Gerhard Vogel, editor; Springer-Verlag, New York, 2002; pp. 702-706).

The usefulness of histamine H₄ receptor ligands in treating pain hasbeen demonstrated (U.S. patent application Ser. No. 11/863,925; alsoCoruzzi, et al, Eur. J. Pharmacol. 2007, Vol. 563, pp. 240-244). Thisinvention discloses the novel utility of the compounds of the inventionto treat pain, including multiple types of pain, including inflammatorypain, non-inflammatory pain, and neuropathic pain. Neuropathic pain isdistinct from other types of pain (e.g. inflammatory pain) in that itcan develop in response to previous or ongoing tissue injury, nerveinjury, or diabetes, but it persists long after signs of the originalinjury or damage have disappeared. Neuropathic pain is not currentlywell treated, and therefore there is a strong need for methods to treatthis particular type of pain. The topic of neuropathic pain has beenreviewed in the scientific literature, for example, Smith, et al., DrugDevelopment Research (2001) Vol. 54(3), pp. 140-153; Collins andChessell, Expert Opinion on Emerging Drugs (2005) vol. 10(1), pp.95-108; Vinik and Mehrabyan, Medical Clinics of North America (2004),vol. 88(4), pp. 947-999; Dray, Urban, and Dickenson, Trends inPharmacological Sciences (1994) vol. 15(6) pp. 190-7; Dworkin, ClinicalJournal of Pain (2002) vol. 18(6) pp. 343-9. There do exist a number ofanimal models of neuropathic pain that can be used to assess the abilityof the compounds of the invention to treat neuropathic pain, asdiscussed herein.

Animal models of neuropathic pain are predictive of efficacy oftreatment of neuropathic pain in humans. These models can be used toassess the efficacy of compounds of the invention in treatingneuropathic pain. Examples of models well known to those skilled in theart include the Chung model (Kim and Chung, Pain (1992) vol. 50 pp.355-363) and the Bennett model (Bennett and Xie, Pain (1988) vol. 30 pp.87-107).

Determination of Analgesic Effect Against Neuropathic Pain

Animals are prepared for testing, by use of a surgical procedure thatinduces neuropathic pain in one paw. Male Sprague Dawley rats can bepurchased from Charles River (Portage, Mich.). Prior to surgery, animalsare housed in groups and maintained in a temperature-regulatedenvironment. Following nerve ligation surgery, animals are housed ingroups and have access to food and water ad libitum.

The L5 and L6 spinal nerves of anesthetized rats are tightly ligated ina manner described previously (see Kim and Chung, Pain (1992) vol. 50pp. 355-363). An incision is made on the dorsal portion of the hip, andthe muscle is blunt-dissected to reveal the spinal processes. The L6transverse process is removed, and the left side L5 and L6 spinal nervesare tightly ligated with 5.0 braided silk suture. The wound is cleaned,the membrane sewn with 4.0 dissolvable Vicryl suture, and the skinclosed with wound clips. The paw affected by the surgical procedure (theleft paw) develops an allodynic response, a hypersensitivity tomechanical and other stimuli; neuropathic pain is assessed as anincreased sensitivity in the surgically affected (left) allodynic pawcompared to the control paw on the right side, and measured by comparingthe response of the (left side) allodynic paw to the response of theunaffected right side control paw.

For the assessment of neuropathic pain, mechanical allodynia in theaffected paw of animals that had undergone spinal nerve ligation can beevaluated using testing with von Frey filaments. As described previouslyby S. R. Chaplan, et al. (“Quantitative assessment of tactile allodyniain the rat paw” J. Neurosci. Meth. (1994) vol. 53 pp. 55-63), two weeksfollowing surgery rats are acclimated to a testing box constructed ofplexiglass with a wire mesh floor which allows access to the plantarsurface of the animal's hindpaws. Using an Up-Down method (Dixon, Ann.Rev. Pharmacol. Toxicol. (1980) vol. 20, pp. 441-462; Chaplan et al.,“Quantitative assessment of tactile allodynia in the rat paw” J.Neuroscience Methods (1994) vol. 53 pp. 55-63), von Frey filaments ofincreasing stiffness are applied to the plantar surface of the hindpaws,and the withdrawal response of the animals is observed; for thesurgically affected paw with neuropathic pain (the left side paw), thebaseline level of allodynia has a withdrawal threshold of ≦4 g ofpressure. By comparison, for the control paw without allodynia (in thiscase, the right side paw), the typical withdrawal pressure is around 15g. The efficacy of the compound in reducing neuropathic pain atdifferent doses is determined by comparing response in thesurgery-affected paw versus the response in the control paw. This isexpressed as the MPE (maximum percent effect), or 100 times thewithdrawal threshold of the allodynic (left side) divided by thewithdrawal threshold of the control (right side).

Determination of Analgesic Effect Against Inflammatory Pain

To assess the effectiveness of representative compounds of the inventionagainst acute model inflammatory pain, animals can be tested in an acutemodel of carrageenan-induced thermal hyperalgesia (see for example,Honore, et al. Behavioural Brain Research 167 (2006) pp. 355-364;Porreca, et al., Journal of Pharmacology and Experimental Therapeutics(2006) vol. 318 pp. 195-205). Carrageenan is injected into the test pawof the animal, and after 90 minutes, the test drug is administered byintraperitoneal dosing; the effect on thermal hyperalgesia is assessedin a hotbox assay which is done 30 minutes after the intraperitonealdosing of the test drug. The MPE (maximal percent effect) is reported bycomparison to the control paw (not injected with carrageenan), MPE beingexpressed as 100 times the withdrawal latency of the carrageenaninjected paw (in seconds) divided by the withdrawal latency of thecontrol (not injected with carrageenan) paw.

Determination of Analgesic Effect Against Pain in a Surgical SkinIncision Model

Analgesic effect against pain can also be determined using a surgicalskin incision model (Joshi, et al., Pain 123 (2006) 75-82). Understerile conditions, animals (rats) are prepared for testing bysubjecting them to a surgical procedure, where the plantaris muscle iselevated and incised longitudinally with the origin and insertion of themuscle remaining intact. The skin is then closed with two mattresssutures (e.g. 5-0 nylon sutures). After surgery, animals are allowed torecover on a warming plate and are housed individually in cages withsoft bedding. After this surgery, the animals develop a hypersensitivitycalled allodynia (that is, pain due to a stimulus that does not normallyprovoke pain). Animals can be tested for mechanical allodynia using vonFrey hair mechanical stimulation 2, 24, and 48 hours after surgery asdescribed for the Chung model.

Compounds of the invention are histamine H₄ receptor ligands thatmodulate function of the histamine H₄ receptor by altering the activityof the receptor. These compounds may be antagonists that block theaction of receptor activation induced by histamine H₄ receptor agonistssuch as histamine; they may be histamine H₄ receptor inverse agoniststhat inhibit the basal activity of the receptor and block the action ofreceptor activation induced by histamine H₄ receptor agonists such ashistamine; and they may be partial agonists that partially block theaction of receptor activation induced by histamine H₄ receptor agonistssuch as histamine and prevent full activation of histamine H₄ receptors.

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents. Various changes andmodifications to the disclosed embodiments will be apparent to thoseskilled in the art. Such changes and modifications, including withoutlimitation those relating to the chemical structures, substituents,derivatives, intermediates, syntheses, formulations, or methods, or anycombination of such changes and modifications of use of the invention,may be made without departing from the spirit and scope thereof.

1. A compound of formula (I):

or a pharmaceutically acceptable, salt, ester, amide, or prodrugthereof, wherein: G¹ is selected from oxygen, sulfur, S(O), S(O)₂, NR⁸and alkylene; G² is selected from oxygen, sulfur, S(O), S(O)₂, NR⁸, andalkylene; wherein each carbon of the alkylene groups of G¹ and G² may beoptionally substituted with one or more groups selected from acyl,acyloxy, alkenyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonyl,alkyl, alkylcarbonyl, alkylcycloalkyl, alkylsulfonyl, alkylthio,alkynyl, amido, carboxy, cyano, cyanoalkyl, cycloalkoxyalkyl,cycloalkyl, fluorine, fluoroalkoxy, fluoroalkyl, fluorocycloalkyl,fluorocycloalkylalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxy,hydroxyalkyl, mercapto, nitro, and oxo; provided that only one of G¹ orG² can be oxygen, sulfur, S(O), S(O)₂ or NR⁸; G⁴ is CH₂ or a bond; R¹ isselected from hydrogen, NH₂, —NH(acyl), —NH(alkyl), —N(alkyl)₂,—NH(C═O)aryl, —NH-alkylene(NR⁸R⁹), —NH(C═O)-alkylene(NR⁸R⁹),—NR⁸(C═O)NR⁸R⁹, —NH-alkylene-heteroaryl, —NHOH, —NHOCH₃,—O-alkylene(NR⁸R⁹), alkoxy, alkoxycarbonyl, alkyl, carboxy,—(C═O)—(NR⁸R⁹), —(C═O)—NH-alkylene(NR⁸R⁹), cyano, cyanoalkyl,cycloalkyl, fluoroalkyl, fluorocycloalkyl, hydroxyalkyl, and piperazine;R⁶ at each occurrence is independently selected from hydrogen,alkoxyalkyl, alkyl, alkylcycloalkyl, cyanoalkyl, cycloalkoxyalkyl,cycloalkyl, fluoroalkyl, fluorocycloalkyl, fluorocycloalkylalkyl, andhydroxyalkyl; R⁷ at each occurrence is independently is selected fromalkoxyalkyl, fluoroalkyl, fluorocycloalkyl, fluorocycloalkylalkyl, andhydroxyalkyl; R⁸ and R⁹ each are each independently selected from acyl,alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcycloalkyl,alkylsulfonyl, amido, aryl, cyanoalkyl, cycloalkoxyalkyl, cycloalkyl,fluorocycloalkyl, fluorocycloalkylalkyl, heteroaryl, heterocycle,hydrogen, formyl, hydroxy, and hydroxyalkyl; R¹⁰ and R¹¹ taken togetherare alkylene, —OCH₂CH₂O—, —OCH₂CH₂CH₂O—, —CH₂CH₂OCH₂CH₂—, or

A¹ is a group of structure A² or A³; wherein A² is selected from

and A³ is selected from

wherein G³ is O, S, S(O), S(O)₂; n is 1, 2, or 3; m is 0, 1, or 2; andwherein each carbon atom of groups A¹ may be optionally substituted withone or more groups selected from acyl, acyloxy, alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylcycloalkyl, alkylsulfonyl, alkylthio, alkynyl, amido, carboxy,cyano, cyanoalkyl, cycloalkoxyalkyl, cycloalkyl, fluorine, fluoroalkoxy,fluoroalkyl, fluorocycloalkyl, fluorocycloalkylalkyl, formyl,haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, andnitro.
 2. The compound of claim 1, wherein R¹ is selected from hydrogen,NHOH, —NHOCH₃, alkoxy, cyano, cyanoalkyl, cycloalkyl, fluoroalkyl,fluorocycloalkyl, and hydroxyalkyl.
 3. The compound of claim 1, whereinR¹ is hydrogen, NH₂, —NHCH₃, —NH(C═O)CH₃, —NH(C═O)phenyl, —NH(C═O)NHCH₃,—NH(C═O)CH₂NH₂, —NH(C═O)CH₂NHCH₃, —NH(C═O)CH₂N(CH₃)₂,—NH(C═O)CH₂CH₂CH₂NH₂, —NHCH₂(pyridin-3-yl), —NHCH₂(imidazol-4-yl),—NHCH₂CH₂N(CH₃)₂, piperazin-1-yl, —(C═O)OCH₃, or —(C═O)OH.
 4. Thecompound of claim 1, wherein G⁴ is a bond.
 5. The compound of claim 1,wherein G¹ is oxygen, sulfur, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, or—CH₂CH₂CH₂CH₂—, and wherein G⁴ is a bond.
 6. The compound of claim 1,wherein G² is oxygen, sulfur, —CH₂—, —CH₂CH₂—, or —CH(CH₃)—, and whereinG⁴ is a bond.
 7. The compound of claim 1, wherein R¹⁰ and R¹¹ takentogether are —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂—,—CH₂CH₂CH₂CH₂CH₂CH₂—, —OCH₂CH₂O—, —OCH₂CH₂CH₂O—, —CH₂CH₂OCH₂CH₂—, or


8. The compound of claim 1, wherein A¹ is a group of the formula:


9. The compound of claim 1, wherein the compound is selected form thegroup consisting of:(R)-4′-(3-(methylamino)pyrrolidin-1-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine;4′-(piperazin-1-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine;4′-(3-(methylamino)azetidin-1-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine;(R)-4′-(3-aminopyrrolidin-1-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine;(S)-4′-(3-aminopyrrolidin-1-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine;4′-((3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine;4′-((3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine;4′-(1,4-diazepan-1-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine;4′-((4aR,7aR)-tetrahydro-1H-pyrrolo[3,4-b]pyridin-6(2H,7H,7aH)-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine;N4′-(1-methylpiperidin-4-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazoline]-2′,4′-diamine;methyl4-amino-1-(2′-amino-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazoline]-4′-yl)piperidine-4-carboxylate;4-amino-1-(2′-amino-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazoline]-4′-yl)piperidine-4-carboxylicacid;4′-(3-aminoazetidin-1-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine;4′-(2-(dimethylamino)ethoxy)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine;(R)-4′-(1-methylpyrrolidin-3-yloxy)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine;4-(piperazin-1-yl)-5,6,7,8-tetrahydrospiro[cyclohepta[d]pyrimidine-9,1′-cyclohexan]-2-amine;(R)-4-(3-aminopyrrolidin-1-yl)-5,6,7,8-tetrahydrospiro[cyclohepta[d]pyrimidine-9,1′-cyclohexan]-2-amine;4-((4aR,7aR)-tetrahydro-1H-pyrrolo[3,4-b]pyridin-6(2H,7H,7aH)-yl)-5,6,7,8-tetrahydrospiro[cyclohepta[d]pyrimidine-9,1′-cyclohexan]-2-amine;4-(piperazin-1-yl)-1′,3′,5,6,7,8-hexahydrospiro[cyclohepta[d]pyrimidine-9,2′-inden]-2-amine;and(R)-4-(3-aminopyrrolidin-1-yl)-1′,3′,5,6,7,8-hexahydrospiro[cyclohepta[d]pyrimidine-9,2′-inden]-2-amine.10. A pharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 11. A method of treating a mammalhaving a condition where modulation of histamine H₄ receptor activity isof therapeutic benefit, said method comprising administering to asubject having or susceptible to said disorder with a therapeuticallyeffective amount of a compound of the formula (I) of claim
 1. 12. Themethod of claim 11, wherein the condition or disorder is asthma,allergy, allergic dermatitis, rheumatoid arthritis, inflammation,inflammatory bowel disease, colitis, ulcerative colitis, Crohn'sdisease, psoriasis, psoriatic arthritis, osteoarthritis, eczema, hives,multiple sclerosis, auto-immune encephalomyelitis, auto-immune disease,scleroderma, lupus, dermatitis, atopic dermatitis, rhinitis, allergicrhinitis, chronic obstructive pulmonary disease, septic shock, acuterespiratory distress syndrome, cancer, pruritis, itching, pain,inflammatory pain, hyperalgesia, inflammatory hyperalgesia, migraine,cancer pain, osteoarthritic pain, post-surgical pain, non-inflammatorypain, neuropathic pain, sub-categories of neuropathic pain includingperipheral neuropathic pain syndromes, chemotherapy-induced neuropathy,complex regional pain syndrome, HIV sensory neuropathy, neuropathysecondary to tumor infiltration, painful diabetic neuropathy, phantomlimb pain, postherpetic neuralgia, postmastectomy pain, trigeminalneuralgia, central neuropathic pain syndromes, central poststroke pain,multiple sclerosis pain, Parkinson disease pain, or spinal cord injurypain, or a combination thereof.
 13. The method of claim 11, wherein thecondition or disorder is asthma.
 14. The method of claim 11, wherein thecondition or disorder is inflammation, inflammatory pain, orinflammatory hyperalgesia, or a combination thereof.
 15. The method ofclaim 11, wherein the condition or disorder is neuropathic pain.
 16. Themethod of claim 11, wherein the condition or disorder is hyperalgesia,migraine, cancer pain, visceral pain, osteoarthritis pain, orpost-surgical pain, or a combination thereof.
 17. A method of treatingpain comprising administering a histamine H₄ receptor ligand of formula(I) according to claim 1, or a salt, ester, amide, or prodrug thereof,in combination with a histamine H₁ antagonist; a histamine H₂antagonist, histamine H₃ antagonist; a modulator of TNF-α, ananti-inflammatory corticocosteroids; a 5-lipoxygenase inhibitor; aleukotriene antagonist; a LTB4 antagonist; a non-steroidalanti-inflammatory drug; a COX-2 inhibitor; a β-adrenergic receptoragonist; an anti-nociceptive opiate agonist, an anti-nociceptive alphaadrenergic agonist, a TRPV1 antagonist, a nicotinic acetylcholinereceptor agonist, a CB-1 agonist; a CB-2 agonist; a P2X7 antagonist; ametabotropic glutamate receptor antagonist; or an adrenergic agonist, ora combination thereof.